Controlled release bioactive agent delivery device

ABSTRACT

The invention provides a controlled release bioactive agent delivery device that includes a body member having a direction of extension, a longitudinal axis along the direction of extension, and a proximal end and a distal end, wherein at least a portion of the body member deviates from the direction of extension, and a polymeric coated composition in contact with the body member, the polymeric coated composition including a first polymer, a second polymer, and a bioactive agent, wherein the first polymer comprises polyalkyl(meth)acrylate, aromatic poly(meth)acrylate, or a combination of polyalkyl(meth)acrylate and aromatic poly(meth)acrylate, and wherein the second polymer comprises poly(ethylene-co-vinyl acetate). The invention also provides methods of delivering a bioactive agent to a patient in a controlled release manner, as well as methods of making a controlled release bioactive agent delivery device.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/467,419, filed May 2, 2003, entitled “CONTROLLED RELEASEBIOACTIVE AGENT DELIVERY DEVICE,” which application is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to a delivery device for controlled delivery ofone or more bioactive agents to a treatment site within the body.

BACKGROUND OF THE INVENTION

Many surgical interventions involve placement of a medical device intothe body. While beneficial for treating a variety of medical conditions,the placement of metal or polymeric devices in the body can give rise tonumerous complications. Some of these complications include increasedrisk of infection, initiation of a foreign body response (which canresult in inflammation and/or fibrous encapsulation), and initiation ofa wound healing response (which can result in hyperplasia and/orrestenosis).

One approach to reducing the potential harmful effects that can resultfrom medical device implantation is to deliver bioactive compounds tothe vicinity of the implanted device. This approach attempts to diminishharmful effects that arise from the presence of the implanted device.For example, antibiotics can be released from the surface of the deviceto minimize infection, and antiproliferative drugs can be released toinhibit hyperplasia. One benefit of the local release of bioactiveagents is the avoidance of toxic concentrations of drugs that aresometimes necessary, when given systemically, to achieve therapeuticconcentrations at the site where they are required.

Further, medical devices can be placed in the body for treatment of amedical condition, such as infection, disease, or the like. In theseinstances, one or more bioactive agents can be released from the deviceto treat the condition, in addition to, or in place of, the bioactiveagents that reduce harmful effects of the implant itself.

Several challenges confront the use of medical devices that releasebioactive agents into a patient's body. For example, treatment mayrequire release of the bioactive agent(s) over an extended period oftime (for example, weeks, months, or even years), and it can bedifficult to sustain the desired release rate of the bioactive agent(s)over such long periods of time. Further, the device surface ispreferably biocompatible and non-inflammatory, as well as durable, toallow for extended residence within the body. Preferred devices intendedfor implantation in the body are manufactured in an economically viableand reproducible manner, and they are preferably sterilizable usingconventional methods.

In particular, placement of implantable devices in limited accessregions of the body can present additional challenges. Limited accessregions of the body can be characterized in terms of physicalaccessibility as well as therapeutic accessibility. Factors that cancontribute to physical accessibility difficulties include the size ofthe region to be reached (for example, small areas such as glands), thelocation of the region within the body (for example, areas that areembedded within the body, such as the middle or inner ear), the tissuessurrounding the region (for example, areas such as the eye or areas ofthe body surrounded by highly vascularized tissue), or the tissue to betreated (for example, when the area to be treated is composed ofparticularly sensitive tissue, such as areas of the brain).

Factors that can contribute to therapeutic accessibility can be seen,for example, in the delivery of drugs to the eye. Ocular absorption ofsystemically administered pharmacologic agents is limited by the bloodocular barrier, namely the tight junctions of the retinal pigmentepithelium and vascular endothelial cells. High systemic doses ofbioactive agents can penetrate this blood ocular barrier in relativelysmall amounts, but expose the patient to the risk of systemic toxicity.Intravitreal injection of bioactive agents (such as drugs) is aneffective means of delivering a drug to the posterior segment of the eyein high concentrations. However, these repeated injections carry therisk of such complications as infection, hemorrhage, and retinaldetachment. Patients also often find this procedure somewhat difficultto endure.

Because description of the invention will involve treatment of the eyeas an illustrative embodiment, basic anatomy of the eye will now bedescribed in some detail with reference to FIG. 5, which illustrates across-sectional view of the eye. Beginning from the exterior of the eye,the structure of the eye includes the iris 38 that surrounds the pupil40. The iris 38 is a circular muscle that controls the size of the pupil40 to control the amount of light allowed to enter the eye. Atransparent external surface, the cornea 30, covers both the pupil 40and the iris 38. Continuous with the cornea 30, and forming part of thesupporting wall of the eyeball, is the sclera 28 (the white of the eye).The conjunctiva 32 is a clear mucous membrane covering the sclera 28.Within the eye is the lens 20, which is a transparent body locatedbehind the iris 38. The lens 20 is suspended by ligaments attached tothe anterior portion of the ciliary body (not illustrated in thefigures). The contraction or relaxation of these ligaments as aconsequence of ciliary muscle actions changes the shape of the lens 20,a process called accommodation, and allows a sharp image to be formed onthe retina 24. Light rays are focused through the transparent cornea 30and lens 20 upon the retina 24. The central point for image focus (thevisual axis) in the human retina is the fovea (not shown in thefigures). The optic nerve 42 is located opposite the lens.

There are three different layers of the eye, the external layer, formedby the sclera 28 and cornea 30; the intermediate layer, which is dividedinto two parts, namely the anterior (iris 38 and ciliary body) andposterior (the choroid 26); and the internal layer, or the sensory partof the eye, formed by the retina 24. The lens 20 divides the eye intothe anterior segment (in front of the lens) and the posterior segment(behind the lens). More specifically, the eye is composed of threechambers of fluid: the anterior chamber 34 (between the cornea 30 andthe iris 38), the posterior chamber 36 (between the iris 38 and the lens20), and the vitreous chamber 22 (between the lens 20 and the retina24). The anterior chamber 34 and posterior chamber 36 are filled withaqueous humor whereas the vitreous chamber 22 is filled with a moreviscous fluid, the vitreous humor.

An implantable medical device that can undergo flexion and/or expansionupon implantation, and that is also capable of delivering atherapeutically significant amount of a pharmaceutical agent or agentsfrom the surface of the device has been described. See U.S. Pat. Nos.6,214,901 and 6,344,035, published PCT Application No. WO99/55396 andU.S. Patent Application Publication Nos. 2002/0032434, 2003/0031780, and2002/0188037.

A therapeutic agent delivery device that is particularly suitable fordelivery of a therapeutic agent to limited access regions, such as thevitreous chamber of the eye and inner ear is described in U.S. PatentApplication Publication No. 2002/0026176 A1.

SUMMARY OF THE INVENTION

The present invention provides devices and methods for providing one ormore bioactive agents to a treatment site within the body in acontrollable manner. The invention can provide particular advantageswhen used to deliver bioactive agent(s) to limited access regions of thebody. Preferred embodiments of the invention relate to devices andmethods for providing bioactive agent(s) to treatment sites in a mannerthat minimizes damage and interference with body tissues and processes.A primary function of the inventive device is to deliver the bioactiveagent(s) to a desired treatment site within the body, and in preferredembodiments, the device itself does not provide any other significantfunction. That is, once the desired treatment of the body has beenaccomplished, the device is preferably removed from the body. Moreover,preferred embodiments of the invention provide a device that isminimally invasive such that risks and disadvantages associated withmore invasive surgical techniques can be reduced.

In one aspect, the invention relates to a controlled release bioactiveagent delivery device comprising (a) a body member having a direction ofextension, a longitudinal axis along the direction of extension, and aproximal end and a distal end, wherein at least a portion of the bodymember deviates from the direction of extension; and (b) a coatingcomposition in contact with the body member, the coating compositioncomprising a bioactive agent. Preferably, the coating composition is apolymeric coating composition.

In another aspect, the invention relates to a controlled releasebioactive agent delivery device comprising (a) a body member having adirection of extension, a longitudinal axis along the direction ofextension, and a proximal end and a distal end, wherein at least aportion of the body member deviates from the direction of extension; and(b) a polymeric coated composition in contact with the body member, thepolymeric coated composition comprising a first polymer, a secondpolymer, and a bioactive agent, wherein the first polymer comprisespolyalkyl(meth)acrylate, aromatic poly(meth)acrylate, or a combinationof polyalkyl(meth)acrylate and aromatic poly(meth)acrylate, and whereinthe second polymer comprises poly(ethylene-co-vinyl acetate).

In another aspect, the invention provides methods for delivering one ormore bioactive agents to an implantation site within a patient in acontrollable manner. In preferred embodiments, the invention providesdevices and methods for providing controlled release of one or morebioactive agents to limited access regions of the body, such as the eye,ear, central nervous system, and the like.

In yet another aspect, the invention provides methods of making acontrolled release bioactive agent delivery device comprising (a)providing a body member having a direction of extension, a longitudinalaxis along the direction of extension, and a proximal end and a distalend, wherein at least a portion of the body member deviates from thedirection of extension; and (b) providing a polymeric coatingcomposition comprising a first polymer, a second polymer, and abioactive agent in contact with the body member, wherein the firstpolymer comprises polyalkyl(meth)acrylate, aromatic poly(meth)acrylate,or a combination of polyalkyl(meth)acrylate and aromaticpoly(meth)acrylate, and wherein the second polymer comprisespoly(ethylene-co-vinyl acetate).

For ease of discussion, reference will repeatedly be made to a“bioactive agent.” While reference will be made to a “bioactive agent,”it will be understood that the invention can provide any number ofbioactive agents to a treatment site. Thus, reference to the singularform of “bioactive agent” is intended to encompass the plural form aswell.

Preferred embodiments of the invention provide the ability to controlrelease of a bioactive agent by manipulation of one or more features ofthe controlled release device, including formulation of the coatingcomposition, duration of time the device is maintained at theimplantation site, and configuration of the device. For example, theformulation of the coating composition can be manipulated to providecontrolled release of the bioactive agent. According to the invention,the coating composition can include any number of individual bioactiveagents. Moreover, the coating composition can include a wide variety oftypes of bioactive agents, as the formulation of the coating composition(for example, the choice and/or ratio of first polymer and secondpolymer) can be manipulated to accommodate a bioactive agent of choice.Further, the amount of bioactive agent included in the coatingcomposition can be manipulated to provide a desired initialconcentration of bioactive agent within the coating composition, therebyproviding a selected therapeutic amount of the bioactive agent to thetreatment site.

The duration of time the device is maintained at the implantation sitecan be varied to provide a desired amount of bioactive agent to atreatment site. For example, preferred embodiments of the inventivedevice are configured to be implanted and explanted from a patient;thus, the device can be removed from the patient at any time aninterventionalist determines a treatment course has been completed.

In some embodiments, the configuration of the device can be manipulatedto control release of the bioactive agent. For example, the surface areaand/or size of the device can be manipulated to control dosage of thebioactive agent(s) provided to the implantation site. In preferredembodiments, the geometry and/or surface area of the body member can bemanipulated by choice of wire diameter, coil spacing, device length,device diameter, and the like. Preferably, the device provides increasedsurface area for delivery of bioactive agent, as compared to asubstantially linear device having the same length and width. Thisincreased surface area can be desirable when the implantation site willbetter accommodate a shorter device (for example, in the eye), or a morenarrow device.

Preferably, the configuration of the controlled release device providesone or more mechanical advantages, such as a built-in anchoringmechanism that reduces or prevents unwanted movement of the devicewithin the body, reduced risk of unwanted ejection of the device fromthe body, and the like. Moreover, preferred embodiments of the inventioncan provide minimally invasive devices and methods for delivering one ormore bioactive agents to a treatment site within the body. Accordingly,the invention can, in some embodiments, reduce risks of infection andcomplications associated with more invasive surgical procedures, as wellas improve recovery time for patients requiring such treatments.

In preferred embodiments, the inventive device is easily retrievablefrom the body, such that the device is placed within the body only forthe required treatment duration, and is removed upon completion of atreatment course. Preferably, the device provides enhanced durability ofthe coated composition, and thus the coated composition (minus thereleased bioactive agent) is removed from the implantation site uponcompletion of a treatment course. This can avoid potential harmfuleffects that could arise if one or more components of the device wereleft within the body beyond the treatment course (for example, if someof the coating is sheared off the device or otherwise delaminates fromthe body member).

Surprisingly, preferred embodiments of the invention provide devices andmethods of reproducibly releasing bioactive agent in a linear mannerover extended periods of time. As described herein, in vitro elutionassays of preferred embodiments of the invention show surprisinglycontrollable release of bioactive agent over time. In preferredembodiments, coating compositions having varying formulations (in termsof polymer ratios) can provide substantially linear release rates ofbioactive agent. Based upon the in vitro data presented herein, it isexpected that in vivo release rates will provide reproducible releaserates in a linear manner over an extended period of time. See Jaffe etal., Safety and Pharmacokinetics of an Intraocular FluocinoloneAcetonide Sustained Delivery Device, Investigative Ophthalmology &Visual Science, 41:3569-3575 (2000). Thus the invention can providecontrolled release of bioactive agent to an implantation site that canbe adjusted to accommodate desired treatment duration and dosage.Because the invention provides local delivery of one or more bioactiveagents to an implantation site, the invention also preferably avoidstoxic levels of bioactive agents that can be required during systemictreatment.

Preferably, the invention provides a surprisingly durable controlledrelease device. Durability can be imparted by material characteristicsof the device, as well as structural features of the inventive device.Regarding material characteristics of the device, for example,durability of the device can be described in terms of the chemicalcomposition of the polymeric coating composition, as well as adherenceof the polymeric coating composition to the body member. In preferredembodiments, the polymeric coating preferably adheres to the body membersufficiently to withstand the effect of shear forces encountered duringimplant and/or explant of the device, which could otherwise result indelamination of the coating from the body member. Such adherence canarise from the chemical composition of the polymeric coating, as well asthe cohesion of the polymeric coating (thus impacting the integrity ofthe coating).

Structural features can also provide preferred durabilitycharacteristics to the inventive device. According to the invention, atleast a portion of the body member deviates from the direction ofextension, thereby providing a device that provides structuraldurability before, during, and after implantation in the body. Thestructure of the body member is preferably chosen to effectivelytranslate force applied by an interventionalist during implantationand/or explantation to provide desired advanceability (described herein)and thus withstand forces that can compromise the structural integrityof the device. Moreover, when the surface of the body member includessurface configurations (for example, micro-etched surfaces, roughenedsurfaces, and the like), adhesion of the polymeric coating compositionto the body member surface can be improved.

Durability of the coating composition can be assessed utilizing suchtechniques as visual inspection of the integrity of the coating on thesurface of the body member (for example, utilizing such commontechniques as microscopic or spectroscopic analysis), weight of thecoating before and after implant/explant, and the like.

These and other aspects and advantages will now be described in moredetail.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several aspects of the inventionand together with the description of the preferred embodiments, serve toexplain the principles of the invention. A brief description of thedrawings is as follows:

FIG. 1 is a perspective view of an implantable device according to oneembodiment of the invention.

FIG. 2 is a view from the bottom of the embodiment illustrated in FIG.1.

FIG. 3 is a perspective view of an implantable device according toanother embodiment of the invention.

FIG. 4 is a view from the bottom of the embodiment illustrated in FIG.3.

FIG. 5 illustrates transcleral placement of an implantable deviceaccording to one embodiment of the invention.

FIG. 6 is a cross-sectional view of an eye illustrating the centralvisual field “A” of the eye.

FIG. 7 is a graph showing in vitro elution of triamcinolone acetonide(TA) into phosphate buffered saline (PBS) for the coated wires preparedand tested as described in Example 1.

FIG. 8 is a graph showing in vitro elution of triamcinolone acetonide(TA) into phosphate buffered saline (PBS) for the helical coils preparedand tested as described in Example 2.

FIG. 9 is a graph showing in vivo elution of triamcinolone acetonide(TA) for the helical coils prepared and tested as described in Example3.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention described below are notintended to be exhaustive or to limit the invention to the precise formsdisclosed in the following detailed description. Rather, the embodimentsare chosen and described so that others skilled in the art canappreciate and understand the principles and practices of the presentinvention.

Various terms relating to the systems and methods of the invention areused throughout the specification.

As used herein, a “coating composition” refers to one or more vehicles(for example, solutions, mixtures, emulsions, dispersions, blends, andthe like) used to effectively coat a surface. A “coated composition”refers to the effective combination of bioactive agent, first polymer,and second polymer on a surface of the controlled delivery device. Thecoated composition can be formed from one or more coating compositions,or in one or more layers, as will be apparent from the teaching herein.

As used herein, “biocompatible” means the ability of an object to beaccepted by and to function in a recipient without eliciting asignificant foreign body response (such as, for example, an immune,inflammatory, thrombogenic, or the like response). For example, whenused with reference to one or more of the polymers of the invention,biocompatible refers to the ability of the polymer (or polymers) to beaccepted by and to function in its intended manner in a recipient.

As used herein, “therapeutically effective amount” refers to that amountof a bioactive agent alone, or together with other substances (asdescribed herein), that produces the desired effect (such as treatmentof a medical condition such as a disease or the like, or alleviation ofpain) in a patient. During treatment, such amounts will depend upon suchfactors as the particular condition being treated, the severity of thecondition, the individual patient parameters including age, physicalcondition, size and weight, the duration of the treatment, the nature ofthe particular bioactive agent thereof employed and the concurrenttherapy (if any), and like factors within the knowledge and expertise ofthe health practitioner. A physician or veterinarian of ordinary skillcan readily determine and prescribe the effective amount of thebioactive agent required to treat and/or prevent the progress of thecondition.

The term “implantation site” refers to the site within a patient's bodyat which the implantable device is placed according to the invention. Inturn, a “treatment site” includes the implantation site as well as thearea of the body that is to receive treatment directly or indirectlyfrom a device component. For example, bioactive agent can migrate fromthe implantation site to areas surrounding the device itself, therebytreating a larger area than simply the implantation site. The term“incision site” refers to the area of the patient's body (the skin andtransdermal area) at which an incision or surgical cut is made toimplant the device according to the invention. The incision siteincludes the surgical cut, as well as the area in the vicinity of thesurgical cut, of the patient.

The term “treatment course” refers to the dosage rate over time of oneor more bioactive agents, to provide a therapeutically effective amountto a patient. Thus, factors of a treatment course include dosage rateand time course of treatment (total time during which the bioactiveagent(s) is administered).

The present invention is directed to methods and apparatuses foreffectively treating a treatment site within a patient's body, and inparticular for delivering bioactive agents to a limited access region ofa patient's body, such as the eye, ear, spinal cord, brain, and joints.Such methods and apparatuses in accordance with the present inventioncan advantageously be used to provide flexibility in treatment durationand type of bioactive agent delivered to the treatment site. Inparticular, the present invention has been developed for controllablyproviding one or more bioactive agents to a treatment site within thebody for a desired treatment course.

In order to be properly introduced and utilized, implantable devices ofall sorts of types are preferably designed to accommodate needs foradvanceability, manipulability, and crossability to the distal end ofthe device as such is applied to the proximal end of the device. Forpurposes of this application, the following terms are given thefollowing meaning. Advanceability is the ability to transmit force fromthe proximal end of the device to the distal end of the device. The bodymember of the device should have adequate strength for advanceabilityand resistance to buckling or kinking. Manipulability is the ability tonavigate tortuous vasculature or other body passages to reach thetreatment site. A more flexible distal portion is known to improvemanipulability. Thus, it can be desirable to provide a device having abody member with some elastomeric properties to improve flexibility insome applications. Crossability is the ability to navigate the deviceacross tissue barriers or narrow restrictions in the vasculature.

Optimization of advanceability, manipulability, crossability and torquetransmission can be accomplished by carefully choosing the devicematerial and its physical characteristics, such as thickness of thematerial forming the body member. Further, in order to achieve acombination of desired properties at different parts of the deviceitself, the device can be fabricated to combine a plurality ofcomponents together to define a device body member. That is, a portionof the overall length of a body member of the device can comprise adifferent component than another. These one or more portions cancomprise components of different physical characteristics and/ordifferent materials. For example, a distal tip portion can be providedthat is more resilient than the remainder of the device body member forbetter crossability and to provide a softer leading end of the devicefor abutting body internal membranes and the like. Different materialsinclude different metallic materials or polymeric materials from oneanother, for example, or similar polymers of different densities,fillers, crosslinking or other characteristics. In particular, a portionof a device body member can comprise a material chosen for flexibilityto allow flexion of the device during residence within the body (forexample, in such areas as joints, where movement of the tissues in thearea is likely) while another portion can comprise a material chosen foraxial and/or torque transmission.

According to the present invention, a device has been developed that canbe used to treat any implantation site within the body in which it isdesirable to provide controlled release of one or more bioactive agents.In preferred embodiments, the device can be used to provide one or morebioactive agents to a treatment site that comprises a limited accessregion of the body, such as the eye, ear, brain, spine, and joints. Morespecifically, the device of the invention includes a body member havinga direction of extension and at least a portion of the body memberdeviating from the direction of extension, and a polymeric coatingcomposition in contact with the body member. The body member andpolymeric coating composition are configured to provide controlledrelease of a bioactive agent to a treatment site. As described herein,controlled release at the treatment site can mean control both in dosage(including dosage rate and total dosage) and duration of treatment.

To facilitate the discussion of the invention, use of the invention totreat an eye will be addressed. Eyes are selected as a result of theparticular difficulties encountered when treating medical conditions ofthe eye, as described above. Further, in terms of lowering the risk ofdamage to body tissues while providing a superior device, the advantagesof this controlled release device can be clearly presented. However, itis understood that the device and methods disclosed are applicable toany treatment needs, for example, treatment of limited access regions ofthe body where controlled release of a bioactive agent is desired duringtreatment, such as, for example, the central nervous system (the brainand spinal cord), the ear (such as the inner ear), and joints.

In one aspect, the invention provides a controlled release bioactiveagent delivery device comprising: (a) a body member having a directionof extension, a longitudinal axis along the direction of extension, anda proximal end and a distal end, wherein at least a portion of the bodymember deviates from the direction of extension; and (b) a polymericcoated composition in contact with the body member, the polymeric coatedcomposition comprising a first polymer, a second polymer, and abioactive agent, wherein the first polymer comprisespolyalkyl(meth)acrylate, aromatic poly(meth)acrylate, or a combinationof polyalkyl(meth)acrylate and aromatic poly(meth)acrylate, and whereinthe second polymer comprises poly(ethylene-co-vinyl acetate).

Generally speaking, the body member of the implantable device is theportion of the controlled release device that is inserted into apatient. The body member can be described as including a proximal end(which is located, upon implantation, towards the exterior of the body),a distal end (which is located, upon implantation, towards the interiorof the body), and a longitudinal axis. In use, at least a portion of thebody member is inserted into a patient's body. For example, in someembodiments, it can be preferable to position less than 100% of the bodymember inside the patient's body. The amount of the body memberpositioned within the body can be determined by the interventionalist,based upon such factors as desired treatment parameters, the particularconfiguration of the device, the implantation site, and the like.

The body member further includes a direction of extension, and inpreferred embodiments, at least a portion of the body member deviatesfrom the direction of extension. In preferred embodiments, the bodymember includes at least two, three, four, five, six, seven, eight,nine, ten, or more deviations from the direction of extension. In somealternative embodiments, where the body does not include multipledeviations from the direction of extension, the body member can beprovided in a “J” or a hook-type configuration.

The deviations from the direction of extension can be provided in anysuitable configuration. Exemplary embodiments of such deviations will bedescribed herein for illustrative purposes only, and without intendingto be bound by any particular embodiment described herein. Thedeviations need not be rounded or arcuate. For example, in someembodiments, the body member is provided with a Z-shaped configuration,such that the deviations are angular. Moreover, the deviations need notbe in a regular pattern, but can alternatively be provided in a randommanner, such that the body member contains random curls or turns. Insome embodiments, the deviations are provided in a patternedconfiguration about the longitudinal axis. Examples of these patternedembodiments include coils, spirals, or patterned Z-shaped turns in thebody. Alternatively, the deviations can be provided in a random ornon-patterned configuration about the longitudinal axis. According tothese particular non-patterned embodiments, the distance of theindividual deviations from the longitudinal axis to the outermostperiphery of the body member can be selected to provide a desiredoverall profile of the body member, depending upon the application ofthe device. For example, it can be desirable, in some applications, toprovide an overall profile of the body member having an hourglass shape,alternating ring circumference shapes, and the like.

In some embodiments, the deviations from the direction of extension canbe provided in the form of rings. Such individual rings can beconcentric (that is, having a common axis, or being coaxial about thelongitudinal axis) or eccentric (deviating from a circular path).According to these embodiments, the individual rings are noncontiguousalong the body member length, thereby forming individual ribs atpositions along the direction of extension of the body member.

Preferred configurations of the body member are coiled or spiral.Generally, in a coil configuration, the individual rings of the coilrotate about the longitudinal axis, and the overall coil issubstantially symmetrical about the longitudinal axis. A preferred coilis composed of multiple rings that are substantially similar incircumference along the length, from proximal to distal, of the device.In some preferred embodiments, the rings form a spiral pattern, whereinthe circumference of the rings changes over the length of the device.Preferably, the circumference of the rings decreases toward the distaldirection of the device, so that the largest ring circumference islocated at the proximal region of the device, and the smallest ringcircumference is located at the distal region of the device.

Inclusion of deviating portions of the body member provides an increasedsurface area for delivery of a bioactive agent to an implantation siteas compared to a linear device having the same length and/or width. Thiscan provide advantages during use of the device, since thisconfiguration allows a greater surface area to be provided in a smallerlength and/or width of the device. For example, in some applications, itcan be desirable to limit the length of the device. For example, as willbe discussed in more detail herein, it is desirable to limit the lengthof implants in the eye to prevent the device from entering the centralvisual field of the eye and to minimize risk of damage to the eyetissues. By providing a body member that has at least a portion of thebody member deviating from the direction of extension, the device of theinvention has greater surface area (and thus can hold a greater volumeof bioactive agent) per length of the device without having to make thecross section of the device, and thus the size of the insertionincision, larger.

Still further, in preferred embodiments, the shape of the body membercan provide a built-in anchoring system that reduces unwanted movementof the device and unwanted ejection of the device out of the patient'sbody, since the shape of the body member requires manipulation to removeit from an incision. For example, for a coil-shaped body member, thedevice would require twisting, and a Z-shaped body member would requireback and forth movement, to remove the device from the implantationsite. According to some preferred embodiments, the device does notrequire additional anchoring mechanisms (such as suturing) to the bodytissues, as a result of the self-anchoring characteristics of the deviceitself. As described in more detail herein, inclusion of a cap 8 on thedevice can provide further anchoring features of the device.

In some embodiments, when the body member includes two or moredeviations from the direction of extension, the spacing of theindividual deviations can be selected to provide an optimum combinationof such features as increased coatable surface area, overall dimensionsof the device, and the like. For example, when the body member isprovided in the form of a coil that includes two or more deviations fromthe direction of extension, the distance between the individual coilscan be selected to be equal to or greater than the diameter of thematerial forming the body member. In some aspects, if the distancebetween coils is less than the diameter of the material forming the bodymember, the amount of coatable surface area of the body member candecrease, since it can be more difficult to access portions of thesurface area of the body member with the coating compositions. In oneillustrative embodiment of this aspect of the invention, the body memberis formed of a material having a diameter of 0.5 mm, and the distancebetween each coil of the body member is at least 0.5 mm. Theseprincipals can be applied to any configuration of the body member and isnot limited to coiled configurations.

The overall dimensions of the implantable device can be selectedaccording to the particular application. For example, the length and/orwidth of the device can be selected to accommodate the particularimplantation site. Some factors that can affect the overall dimensionsof the implantable device include the potency of any bioactive agent tobe delivered (and thus the volume of bioactive agent required, whichimpacts the surface area of the device, as discussed herein), thelocation of the implantation site within the body (for example, how farwithin the body the implantation site is located), the size of theimplantation site (for example, a small area such as the eye or innerear, or a larger area, such as a joint or organ area), the tissuesurrounding the implantation site (for example, vascular tissue or hard,calcinous tissue, such as bone), and the like.

By way of example, when the implantable device is used to deliverbioactive agent(s) to the eye, the device is preferably designed forinsertion through a small incision that requires few or no sutures forscleral closure at the conclusion of the surgical procedure. As such,the device is preferably inserted through an incision that is no morethan about 1 mm in cross-section, for example, in the range of about0.25 mm to about 1 mm in diameter, preferably in the range of about 0.25mm to about 0.5 mm in diameter. As such, the cross-section of thematerial forming the body member 2 is preferably no more than about 1mm, for example, in the range of about 0.25 mm to about 1 mm indiameter, preferably in the range of about 0.25 mm to about 0.5 mm indiameter. When the material forming the body member 2 is notcylindrical, the largest dimension of the cross-section can be used toapproximate the diameter of the body member for this purpose, forexample, when the body member cross-section is square.

When used to deliver bioactive agent(s) to the eye, the body member ofthe controlled release device preferably has a total length from itsproximal end to its distal end that is less than about 1 cm, forexample, in the range of about 0.25 cm to about 1 cm. Upon implantation,the body member is positioned within the eye, such that the portion ofthe controlled delivery device that delivers bioactive agent to the eyechamber is positioned near the posterior segment of the eye. When thecontrolled delivery device includes a cap 8, the cap is preferablyprovided with a thickness of less than about 1 mm, more preferably lessthan about 0.5 mm. According to this particular embodiment, the totallength of the controlled delivery device is less than about 1.1 cm,preferably less than about 0.6 cm.

Turning to FIG. 1, a preferred embodiment of the controlled deliverydevice is illustrated. The controlled delivery device includes a bodymember 2 having a proximal end 4 and a distal end 6. FIG. 1 illustratesthe body member in a coil configuration. According to this embodiment,the coil shape of the body member allows the device to be screwed ortwisted into the body through an incision approximately the same size asthe outer diameter of the material forming the body member 2. Stillfurther, the coil shape of the body member can act as an anchoringmechanism to maintain the controlled delivery device within theimplantation site, and can prevent unwanted movement of the device andunwanted ejection of the device from the implantation site and/or thebody. As a result of the coil shape, the controlled delivery device istwisted and unscrewed out of the body during removal of the device.

The distal end 6 of the body member 2 can be positioned at any desirablelocation relative to the longitudinal axis of the body member. As shownin FIGS. 1 and 2, the distal end 6 of the body member according to oneembodiment of the invention can include a tip 10 that is spaced from thelongitudinal axis. This configuration is similar to a standard “corkscrew” type configuration. In use, the device is inserted through theincision site and then twisted until the controlled delivery device isproperly positioned at the treatment site.

Another embodiment is shown in FIGS. 3 and 4, wherein the distal end 6of the body member includes tip 10 that is positioned at thelongitudinal axis of the body member 2. In some embodiments, placementof the tip 10 of the body member 2 at the longitudinal axis can provideadvantages, such as ease of insertion of the device at the distal end.It will be readily apparent that various other configurations of thedistal end of the body member can be provided, depending upon thedesired application.

Further, the proximal end 4 of the body member 2 can also be positionedat any desirable location relative to the longitudinal axis of the bodymember. FIGS. 1 and 3 illustrate the proximal end 4 of the body memberas spaced from the longitudinal axis. However, the proximal end 4 of thebody member can be provided at the longitudinal axis as well (not shownin the figures). In some embodiments, placement of the proximal end 4 ofthe body member 2 at the longitudinal axis can provide advantages, suchas ease of fabrication of the device, increased mechanical strength,improved translation of force (since a uniform force can be applied andtranslated to the body member, with less risk of bending or otherdeformation of the body member), and the like.

In general, materials used to fabricate the body member 2 are notparticularly limited. In some embodiments, the body member 2 can befabricated of a flexible material, so that small movements of thecontrolled delivery device will not be translated to the implantationsite. In some embodiments, as described in further detail herein, it canbe preferable to fabricate at least the distal end 6 of the body member2 of a rigid, non-pliable material. For example, when the device isdesigned for implantation in the eye, it is preferable to fabricate thedevice of a rigid material, to provide improved implant/explantcharacteristics to the device. In some embodiments, as described herein,it can be preferable to fabricate the body member 2 of a material havingshape memory and/or superelastic characteristics.

In some embodiments, the body member 2 can be fabricated from anysuitable material used to manufacture medical devices, such as, forexample, stainless steel (for example, 316L); platinum; titanium; andgold; and such alloys as cobalt chromium alloys, nitinol, or the like.In further embodiments, suitable ceramics can be used to fabricate thebody member 2, such as, for example, silicon nitride, silicon carbide,zirconia, alumina, glass, silica, sapphire, and the like. In stillfurther embodiments, the body member 2 can be fabricated of a suitablecomposite material, such as composite materials commonly used tofabricate implantable devices. Such composite materials can, in someembodiments, provide such advantages as increased strength of thematerial, as well as increased flexibility. Examples of suitablecomposite materials include polymers or ceramics (such as high densitypolyethylene (HDPE), ultra high molecular weight polyethylene (UHMWPE),polymethylmethacrylate bone cement (PMMA), dental polymer matrix (suchas crosslinked methacrylate polymers), and glass-ceramics) reinforcedwith fibers or particulate material (such as carbon fibers, boneparticles, silica particles, hydroxyapatite particles, metal fibers orparticles, or zirconia, alumina, or silicon carbide particles).Nano-composite materials are also contemplated.

In one embodiment, the body member 2 is fabricated of a nonbiodegradablepolymer. Such nonbiodegradable polymers are well known and can include,for example, oligomers, homopolymers, and copolymers resulting fromeither addition or condensation polymerizations. Examples of suitableaddition polymers include, but are not limited to, acrylics such asthose polymerized from methyl acrylate, methyl methacrylate,hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylic acid,methacrylic acid, glyceryl acrylate, glyceryl methacrylate,methacrylamide, and acrylamide; and vinyls such as ethylene, propylene,styrene, vinyl chloride, vinyl acetate, and vinylidene difluoride.Examples of condensation polymers include, but are not limited to,nylons such as polycaprolactam, polylauryl lactam, polyhexamethyleneadipamide, and polyhexamethylene dodecanediamide, as well aspolyurethanes, polycarbonates, polyamides, polysulfones, poly(ethyleneterephthalate), polylactic acid, polyglycolic acid,polydimethylsiloxanes, and polyetherketone. Other suitablenonbiodegradable polymers include silicone elastomers; silicone rubber;polyolefins such as polypropylene and polyethylene; homopolymers andcopolymers of vinyl acetate such as ethylene vinyl acetate 2-pyrrolidonecopolymer; polyacrylonitrile butadiene; fluoropolymers such aspolytetrafluoroethylene and polyvinyl fluoride; homopolymers andcopolymers of styrene acrylonitrile; homopolymers and copolymers ofacrylonitrile butadiene styrene; polymethylpentene; polyimides; naturalrubber; polyisobutylene; polymethylstyrene; latex; and other similarnonbiodegradable polymers.

At least a portion of the body member 2 can deviate from the directionof extension prior to, during, and after insertion of the device in thebody. Alternatively, the device can be fabricated of a material havingshape memory and/or superelastic characteristics that allow the deviceto be deformed into a configuration that is more easily inserted intothe body. In one such embodiment, for example, the body member can bedeformed into a substantially linear configuration, for insertion intothe body. According to this particular embodiment, the body member canreturn to its original shape after it is inserted into the body. In thisembodiment, the body member of the device has a “memory shape” that itwill assume under certain conditions. For example, the body member canhave a zigzag or coiled memory shape. When the interventionalist desiresto implant the device into the body, the interventionalist can deformthe device into a substantially linear shape for insertion of the devicethrough an incision the size of the cross section of the linear shapeddevice. Upon implantation of the device into the body, the device canthen resume its zigzag, coiled, or other memory shape. Preferably, theoverall dimensions of the controlled delivery device (the maximum lengthand width) according to these shape memory embodiments do notsignificantly change by virtue of utilization of the shape memorymaterial and deformation of the body member for implantation and/orexplantation of the device in the body.

Shape memory alloys generally have at least two phases, namely, amartensite phase, which has a relatively low tensile strength and whichis stable at relatively low temperatures, and an austenite phase, whichhas a relatively high tensile strength and which is stable attemperatures higher than the martensite phase. The shape memorycharacteristics are imparted to the material by heating the material toa temperature above the temperature at which the austenite phase isstable. While the material is heated to this temperature, the device isheld in the “memory shape,” which is the shape that is desired to be“remembered.” Materials having shape memory and/or superelasticcharacteristics are well known and can include, for example, shapememory alloys (SMA) such as nitinol (a nickel-titanium alloy), and shapememory polymers (SMP) such as AB-polymer networks based uponoligo(e-caprolactone) dimethylacrylates and n-butyl acrylate. Suchmaterials and methods of imparting shape memory characteristics areknown and will not be described further herein.

Preferably, the controlled delivery device of the invention takesadvantage of the material properties of the body member (for example,superelastic properties) to extend the body member into a linear shape.Once placed at the implantation site in an unconstrained form, the bodymember can resume its memory shape.

The distal end 6 of the body member can include any suitableconfiguration, depending upon the application of the device and the siteof the body at which the device is to be implanted. For example, in someembodiments, the distal end 6 can be blunt or rounded. In preferredembodiments, the distal end 6 of the body member is configured to piercethe body during implantation of the device into the body. For example,the distal end 6 of the body member can include a sharp or pointed tip.In one preferred embodiment, the distal end 6 of the body member has aramp-like angle. Preferably, the device according to this embodiment canbe utilized to make an incision in the body, rather than requiringseparate equipment and/or procedures for making the incision site. Ifthe distal end 6 of the body member 2 is used to pierce the body duringinsertion, at least the distal end 6 is preferably fabricated of arigid, non-pliable material suitable for piercing the body. Suchmaterials are well known and can include, for example, polyimide andsimilar materials. In one such preferred embodiment, the distal end 6 ofthe body member 2 is utilized to pierce the eye for insertion of thecontrolled delivery device in the interior of the eye.

In another preferred embodiment, the distal end 6 of the body member 2can be shaped or bent to form a portion (for example, the distal-mostportion of the body member) that is parallel to the longitudinal axis.In one embodiment illustrated in FIGS. 3 and 4, for example, the distalend 6 includes a sharp or pointed tip that is parallel to thelongitudinal axis. According to this particular embodiment, the tiplocated at the distal end 6 of the body member is perpendicular to theplane of incision, thus providing a self-starting tip of the device.While these figures illustrate a sharp tip of the body member, it isunderstood that any suitable configuration of the distal tip can beprovided, utilizing the teaching herein.

The body member 2 can be fabricated from a solid material (a materialthat does not contain a lumen) or a material containing a lumen, asdesired. In the embodiment illustrated in FIGS. 1 to 4, for example, thebody member 2 is fabricated from a solid material that is shaped into acoil. Alternatively, the body member 2 can be fabricated from a tubularmaterial that includes a lumen. The choice of a solid orlumen-containing material is not critical to the invention and can bedetermined based upon availability of materials and processingconsiderations.

When included, the lumen(s) can extend along the length of the bodymember 2 or only a portion of the length of the body member 2, asdesired. In some embodiments, the lumen(s) can serve as a deliverymechanism for delivery of a desired substance to the implantation site.The substance delivered via the lumen can comprise any of the bioactiveagents described herein. The substance delivered via the lumen can bethe same or different bioactive agent(s) from that included in thecoating composition. Further, the substance can be provided in additionto the bioactive agent of the polymeric coating composition, or in placeof the bioactive agent. For example, in one embodiment, one or moresubstances can be delivered via the lumen, and one or more bioactiveagents can be provided to the implantation site from the coatedcomposition.

In some embodiments, the lumen can contain a polymeric coatedcomposition as described herein. According to these particularembodiments, the body member of the device can be provided with orwithout a coating on its external surface. In some such embodiments, thelumen can be utilized to deliver the bioactive agent(s) to theimplantation site. For example, the lumen can contain the polymericcoated composition, including first polymer, second polymer, andbioactive agent. According to this particular embodiment, the bodymember can be provided with a coating on an external surface comprisingthe first polymer and second polymer only (that is, lacking anybioactive agent). Thus, the bioactive agent is provided to theimplantation site in this embodiment principally via the lumen of thebody member. In other embodiments, the lumen can include the inventivepolymeric coated composition (including first polymer, second polymer,and bioactive agent), and the body member is not provided with a coatedcomposition on its external surface.

The lumen can contain any combination of elements, as desired. Forexample, in some embodiments, the lumen can include only the substanceto be delivered. In other embodiments, the lumen can include thesubstance to be delivered, as well as the polymeric coated composition.The particular combination of elements to be included in the lumen canbe selected depending upon the desired application of the device.

When the lumen is to be provided with a substance and/or polymericcoating composition, the lumen can be filled with the desired substanceand/or polymeric coating composition prior to inserting the device intothe body, or after the device has been inserted into the body. When itis desired to fill the device with the substance after insertion intothe body, a port can be provided near the proximal end 4 of the bodymember 2 for such purpose. The port is in fluid communication with thelumen(s) of the body member and can also be used for refilling thedevice with the substance and/or polymeric coating composition afterimplantation, when desired.

When the device includes a port, the port is preferably designed suchthat the needle of an injection mechanism (for example, a syringe) canbe inserted into the port and the material to be included in the lumeninjected by the injection mechanism. Thus, the material can travelthrough the port and into the lumen(s) of the body member. The portpreferably forms a snug seal about the needle of the injection mechanismto prevent leakage of the material out of the port around the injectionmechanism and to provide sterile injection of material into thelumen(s). If desired, fittings or collars (not shown), through which aninjection mechanism can be inserted and which form a snug seal about theinjection mechanism, can be mounted on the port. Upon injection of thematerial into the delivery device, the needle of the injection mechanismis removed from the port and the port sealed. Sealing can beaccomplished by providing a removable cover (not shown) on the port thatcan be removed for injection of the substance and replaced when thematerial has been injected. In a preferred embodiment, the port isfabricated of a self-sealing material through which the injectionmechanism can be inserted and which seals off automatically when theinjection mechanism is removed. Such materials are known and include,for example, silicone rubber, silicone elastomers, polyolefin, and thelike.

In further embodiments, when the device includes more than one lumen,the device can include more than one port. For example, each lumen canbe in fluid communication with a plurality of ports. These ports aresimilar to the single port described above. If desired, the lumens andports can be arranged such that each lumen can be filled with adifferent material through a corresponding port (for example, each lumenhas its own dedicated port). It can be desirable to include more thanone lumen when it is desirable to deliver more than one additionalmaterial to the implantation site.

In embodiments where it is desired to deliver one or more additionalsubstances to the implantation site via one or more lumens, theindividual lumens can include one or more apertures to allow suchdelivery. In one embodiment, such apertures are provided at the distalend 6 of the device. In other embodiments, the apertures are providedalong the length of the body member 2. The number and size of theapertures can vary depending upon the desired rate of delivery of thesubstance (when provided) and can be readily determined by one of skillin the art. The apertures are preferably designed such that thesubstance to be delivered is slowly diffused rather than expelled as afluid stream from the device. For example, when the device is implantedin the eye, it is preferable to deliver the substance through slowdiffusion rather than expulsion of the substance as a fluid stream,which can damage the delicate tissues of the eye. In some embodiments,the polymeric coating composition in contact with the body can provide aparticular porosity to the substance and can assist in controlling therate of diffusion of the substance from the lumen. When included in thedevice, the particular location of the apertures can be situated so asto deliver the substance at a particular location once the device isimplanted into the body.

In another embodiment, when the body member 2 includes a lumen fordelivery of an additional substance to the implantation site, thematerial forming the body member 2 can be chosen to be permeable (orsemi-permeable) to the substance to be delivered from the lumen.According to this particular embodiment, the material can be chosendepending upon the particular application of the device and thesubstance to be delivered and can be readily determined by one of skillin the art. Examples of suitable permeable materials includepolycarbonates, polyolefins, polyurethanes, copolymers of acrylonitrile,copolymers of polyvinyl chloride, polyamides, polysulphones,polystyrenes, polyvinyl fluorides, polyvinyl alcohols, polyvinyl esters,polyvinyl butyrate, polyvinyl acetate, polyvinylidene chlorides,polyvinylidene fluorides, polyimides, polyisoprene, polyisobutylene,polybutadiene, polyethylene, polyethers, polytetrafluoroethylene,polychloroethers, polymethylmethacrylate, polybutylmethacrylate,polyvinyl acetate, nylons, cellulose, gelatin, silicone rubbers, porousfibers, and the like.

According to these particular embodiments, the material used tofabricate the body member 2 can be chosen to provide a particular rateof delivery of the substance, which can be readily determined by one ofskill in the art. Further, the rate of delivery of the substance can becontrolled by varying the percentage of the body member 2 formed of thepermeable (or semi-permeable) material. Thus, for example, to provide aslower rate of delivery, the body member 2 can be fabricated of 50% orless permeable material. Conversely, for a faster rate of delivery, thebody member 2 can be fabricated of greater than 50% of permeablematerial. When one or more portions of the body member 2, rather thanthe whole body member 2, is fabricated of a permeable or semi-permeablematerial, the location of the permeable or semi-permeable material canbe situated so as to deliver the substance at a particular location oncethe device is implanted at the implantation site.

In another embodiment, the lumen of the body member 2 can includeimpermeable dividers located along the length of the lumen. Thus, thelumen of the body member can contain a plurality of compartments, eachof which can be filled with a different substance, as desired. Thesecompartments could be filled prior to insertion through an injectionport located, for example, in the side of each compartment. In anotherembodiment, the device can be filled after it is implanted by providinga plurality of conduits, each conduit in fluid communication with acorresponding compartment. These conduits can be provided within thewall of the body member 2, along the circumference of the body member 2.The substances could then be injected through a plurality of ports, eachport in fluid communication with a corresponding conduit. Thus, asubstance could be injected into the first compartment just below thecap 8 by a port in the center of the cap 8, which delivers the substancedirectly into the first compartment. A substance injected into thesecond port, would flow through conduit and would flow through anaperture in the wall of body member 2 into second compartment, and soon. The substance(s) to be delivered can be delivered to theimplantation site via any of the methods described herein for thelumen(s).

In another embodiment, each lumen or compartment (as desired) can bedesigned for selected “opening” or activation by a laser (via heat orphotodisruption). For example, a laser could be used to create aperturesin the walls of the desired lumen and/or compartment when the particularsubstance is to be delivered. As such, release of each substance couldbe controlled upon demand by an interventionalist. Preferably, when alaser is utilized to create such apertures, the wavelength andtemperature are controlled to minimize any effects on the polymericcoating composition.

In preferred embodiments, the body member 2 can be fabricated in a waythat further increases the surface area of the body member, preferablywithout increasing the overall dimensions of the device. For example, inone embodiment, the device can be fabricated of multiple strands ofmaterial that are entwined or twisted around each other to form the bodymember 2 (for example, multiple strands of wire can be twisted aroundeach other to form the body member). According to these particularembodiments, any number of individual strands can be utilized to formthe body member, for example, 2, 3, 4, or more strands. The number ofindividual strands twisted to form the body member can be selecteddepending upon such factors as, for example, the desired diameter of thematerial forming the body member and/or the overall body memberdiameter, the desired flexibility or rigidity of the device duringinsertion and/or implantation, the size of the implantation, the desiredincision size, the material used to form the body member, and the like.

Provision of the polymeric coating composition to the body memberaccording to these embodiments can be achieved in any desirable manner.For example, each individual strand can be provided with a polymericcoating composition prior to twisting the strands to form the bodymember. Alternatively, the individual, uncoated, strands can be twistedto form the body member, and the formed body member can be provided withthe polymeric coating composition.

In another embodiment, the surface area of the body member 2 can beincreased by including surface configurations on the body member 2.According to these embodiments, any suitable type of surfaceconfiguration can be provided to the body member 2, such as, forexample, dimples, pores, raised portions (such as ridges or grooves),indented portions, and the like. Surface configuration can beaccomplished by roughening the surface of the material used to fabricatethe body member 2. In one such embodiment, the surface of the bodymember is roughened using mechanical techniques (such as mechanicalroughening utilizing such material as 50 μm silica), chemicaltechniques, etching techniques, or other known methods. In otherembodiments, surface configuration can be accomplished by utilizing aporous material to fabricate the body member 2. Examples of porousmaterial are described elsewhere herein. Alternatively, materials can betreated to provide pores in the material, utilizing methods well knownin the art. In still further embodiments, surface configuration can beaccomplished by fabricating the body member 2 of a machined material,for example, machined metal. The material can be machined to provide anysuitable surface configuration as desired, including, for example,dimples, pockets, pores, and the like.

In still further embodiments, increased device surface area can beprovided by utilizing a body member configured as a threaded shaft thatis tapered or untapered, as desired. Such threaded shaft embodiments aresimilar to a typical wood screw. The threaded shaft can be fabricatedusing any suitable techniques, such as molding or machining the threadsof the shaft. Further, the threading on the shaft can be a continuousspiral thread that runs continually from the proximal to the distal endof the body member, or the threading can be provided as noncontiguousrings about the body member. Although these particular embodiments canrequire a larger incision site for implantation of the device in apatient, in some applications, the increased surface area provided bythe threaded shaft (discussed in more detail herein) can outweigh thelarger incision required.

In preferred embodiments, surface configuration of the body member 2 canprovide advantages, such as, for example, increased surface area of thebody member for application of the polymeric coating composition,increased durability of the device, increased tenacity of the polymericcoating composition to the body member (for example, by virtue of aroughened surface, increased surface area for adherence, and the like),enhanced removability of the device after a desired treatment duration,and the like.

The body member 2 can include surface configurations along its entirelength, or only a portion of the length of the body member, as desired.

As shown in FIG. 1, the body member 2 is preferably cylindrical inshape, with a circular cross-section. However, the cross-sectional shapeof the body member 2 is not limited and, for example, can alternativelyhave square, rectangular, octagonal or other desired cross-sectionalshapes.

As shown in FIGS. 1 and 3, a preferred embodiment can include a cap 8positioned at the proximal end 4 of the body member 2. When included inthe device, the cap 8 can assist in stabilizing the device onceimplanted in the body, thereby providing additional anchoring featuresof the device. Preferably, the device is inserted into the body throughan incision until the cap 8 abuts the incision on the exterior of thebody. If desired, the cap 8 can then be sutured to the body at theincision site to further stabilize and prevent the device from movingonce it is implanted in its desired location. When the device isimplanted in the eye, for example, the device can be inserted into theeye through an incision until the cap 8 abuts the incision. If desired,the cap 8 can then be sutured to the eye, to provide furtherstabilization as discussed above.

The overall size and shape of the cap 8 is not particularly limited,provided that irritation to the body at the incision site is limited.Preferably, the cap 8 is sized such that it provides a low profile. Forexample, the dimensions of the cap 8 are preferably selected to providea small surface area to accomplish such desired features as additionalanchoring characteristics of the device, without substantiallyincreasing the overall profile of the device upon implantation. In someembodiments, for example, the cap can be covered by a flap of tissue atthe incision site upon implantation, to further reduce potentialirritation and/or movement of the device at the implantation and/orincision sites. One illustrative example described in more detailelsewhere herein is the covering of the cap with a scleral flap uponimplantation of the device in the eye.

Further, while the cap 8 is illustrated with a circular shape, the capcan be of any shape, for example, circular, rectangular, triangular,square, and the like. In order to minimize irritation to the incisionsite, the cap preferably has rounded edges. The cap 8 is designed suchthat it remains outside the implantation site and, as such, the cap 8 issized so that it will not pass into the implantation site through theincision through which the device is inserted.

As described herein, inclusion of a cap 8 in the device can provideadditional anchoring features to the device itself. However, in someembodiments, it can be desirable to further secure the device to provideadditional anchoring or securing features at the implantation site.Thus, when desired, the cap 8 can be further designed such that it canbe easily sutured or otherwise secured to the surface surrounding theincision and can, for example, contain one or more holes (not shown)through which sutures can pass.

The materials used to fabricate the cap 8 are not particularly limitedand include any of the materials previously described for fabrication ofthe body member 2. Preferably, the materials are insoluble in bodyfluids and tissues with which the device comes in contact. Further, itis preferred that the cap 8 is fabricated of a material that does notcause irritation to the portion of the body that it contacts (such asthe area at and surrounding the incision site). For example, when thedevice is implanted into the eye, the cap 8 is preferably fabricatedfrom a material that does not cause irritation to the portion of the eyethat it contacts. As such, preferred materials for this particularembodiment include, by way of example, various polymers (such assilicone elastomers and rubbers, polyolefins, polyurethanes, acrylates,polycarbonates, polyamides, polyimides, polyesters, polysulfones, andthe like), as well as metals (such as those described previously for thebody member).

In some embodiments, the cap 8 can be fabricated from the same materialas the body member 2. Alternatively, the cap 8 can be fabricated from amaterial that is different from the body member 2. The cap 8 can befabricated separately from the body member 2, and subsequently attachedto the body member 2, using any suitable attachment mechanism (such as,for example, suitable adhesives or soldering materials). For example,the cap 8 can be fabricated to include an aperture, into which the bodymember 2 is placed and thereafter soldered, welded, or otherwiseattached. In alternative embodiments, the cap 8 and body member 2 arefabricated as a unitary piece, for example, utilizing a mold thatincludes both components (the body member 2 and cap 8) of the device.The precise method of fabricating the device can be chosen dependingupon such factors as availability of materials and equipment for formingthe components of the device.

In some embodiments, the cap 8 can be provided with a polymeric coatingcomposition. According to these particular embodiments, the polymericcoating composition provided in connection with the cap 8 can be thesame as, or different from, the polymeric coating composition providedin connection with the body member 2. For example, the particularbioactive agent included in the polymeric coating composition for thecap 8 can be varied to provide a desired therapeutic effect at theincision site. Exemplary bioactive agents that could be desirable at theincision site include antimicrobial agents, anti-inflammatory agents,and the like, to reduce or otherwise control reaction of the body at theincision site. It will be readily apparent upon review of thisdisclosure that the first polymer and second polymer can also beselected for the polymeric coating composition provided in connectionwith the cap 8, to provide a desired polymeric coating compositionspecific for the cap, when desired.

In some embodiments, the cap 8 can include a polymeric coatedcomposition that is the same as the polymer coated composition providedin connection with the body member 2. According to these embodiments,the polymeric coating composition can be applied in one step to theentire controlled delivery device (body member and cap), if desired.Alternatively, the polymeric coating composition can be applied to thecap 8 in a separate step, for example, when the cap 8 is manufacturedseparately, and subsequently attached to the body member 2.

According to the invention, a polymeric coated composition is providedin contact with the body member of the device. Preferably, the polymericcoated composition comprises a first polymer, a second polymer, and abioactive agent.

The coated composition is provided in contact with at least a portion ofthe body member of the device. In some embodiments, for example, it canbe desirable to provide the coated composition in contact with theentire surface of the body member. Alternatively, the coated compositioncan be provided on a portion of the body member (such as, for example,an intermediate portion of the body member located between the proximaland distal ends thereof). In some preferred embodiments, for example, itcan be desirable to provide the coated composition in contact with aportion of the body member that does not include a sharp distal tip ofthe body member. This can be desirable, for example, to reduce risk ofdelamination of the coated composition at the sharp tip and/or tomaintain the sharpness of the tip. The amount of the body member that isin contact with the coated composition can be determined by consideringsuch factors as the amount of bioactive agent to be provided at theimplantation site, the choice of first polymer and/or second polymer forthe coated composition, the characteristics of the implantation site,risk of delamination of the coated composition, and the like. Forexample, in some embodiments, it can be desirable to provide the coatedcomposition on portions of the body member other than the proximal anddistal ends of the device, so as to reduce risk of delamination uponimplant and/or explant of the device. Optionally, such delamination canalso be minimized, in some embodiments, by providing a stepped coatingthickness, such that the coating thickness decreases towards theproximal and/or distal ends of the body member. In still furtheroptional embodiments, the body member can be provided with a coatedcomposition at its distal and/or proximal ends that differs from thecomposition of the coating at other portions of the body member. Oneexample of such an embodiment includes a body member having a lubriciouscoating at the distal and/or proximal end of the body member, with adifferent coated composition in the intermediate portion of the bodymember that is located between the proximal and distal ends of the bodymember. Utilizing the concepts described herein, one of skill in the artcan determine the amount of body member to be provided in contact withthe coated composition, and/or the composition of coated compositionprovided at one or more distinct regions of the body member, as desired.

Suitable first polymers, second polymers, and bioactive agents for usein preparing coating compositions in accordance with the invention canbe prepared using conventional organic synthesis procedures and/or arecommercially available from a variety of sources. Preferably, suchpolymers are either provided in a form suitable for in vivo use in acoating composition, or are purified for such use to a desired extent(for example, by removing impurities) by conventional methods availableto those skilled in the art.

A coating composition can be prepared to include a solvent, acombination of complementary polymers (first polymer and second polymer)dissolved in the solvent, and the bioactive agent or agents dispersed inthe polymer/solvent mixture. The solvent is preferably one in which thepolymers form a true solution. The bioactive agent can either be solublein the solvent or form a dispersion throughout the solvent. In use,these embodiments do not require any mixing on the part of the userprior to application of the coating composition to the device. Inpreferred embodiments, the coating composition can provide a one-partsystem that can be applied to the device in one composition. Forexample, U.S. Pat. No. 6,214,901 exemplifies the use of tetrahydrofuran(THF) as a solvent. While THF is suitable, and at times preferred forcertain coating compositions, other solvents can be used in accordancewith the invention as well, including, for example, alcohols (such asmethanol, butanol, propanol, isopropanol, and the like), alkanes (suchas halogenated or unhalogenated alkanes such as hexane and cyclohexane),amides (such as dimethylformamide), ethers (such as dioxolane), ketones(such as methylketone), aromatic compounds (such as toluene and xylene),acetonitrile, and esters (such as ethyl acetate).

The coated composition is preferably biocompatible, such that it resultsin no significant induction of inflammation or irritation when implantedin the body. In addition, the coated composition is preferably usefulunder a broad spectrum of both absolute concentrations and relativeconcentrations of the polymers. In the context of the previous sentence,the physical characteristics of the coated composition (such astenacity, durability, flexibility and expandability) will typically besuitable over a broad range of polymer concentrations. Furthermore, theability of the invention to control the release rates of a variety ofbioactive agents can preferably be manipulated by varying the absoluteand/or relative concentrations of the polymers and/or the bioactiveagent(s).

Turning to the polymeric coating composition itself, in a preferredembodiment, the polymeric coating composition comprises a first polymer,a second polymer, and a bioactive agent. Preferably, the first polymerprovides one or more desirable properties, such as compatibility withthe second polymer and bioactive agent, hydrophobicity, durability,bioactive agent release characteristics, biocompatibility, molecularweight, and commercial availability. Preferably, the first polymercomprises polyalkyl(meth)acrylate, aromatic poly(meth)acrylate, or acombination of polyalkyl(meth)acrylate and aromatic poly(meth)acrylate.

An example of a suitable polyalkyl(meth)acrylate includespoly(n-butyl)methacrylate. In one preferred embodiment, the polymericcoating composition comprises poly(n-butyl)methacrylate (“pBMA”) andpoly(ethylene-co-vinyl acetate) copolymers as the second polymer(“pEVA”). This composition has proven useful with absolute polymerconcentrations in the range of about 0.05% to about 70% by weight of thecoating composition. As used herein “absolute polymer concentration”refers to the total combined concentrations of first polymer and secondpolymer in the coating composition. In one preferred embodiment, thecoating composition comprises polyalkyl(meth)acrylate (such aspoly(n-butyl)methacrylate with a weight average molecular weight in therange of about 100 kilodaltons (kD) to about 1000 kD and a pEVAcopolymer with a vinyl acetate content in the range of about 10% toabout 90% by weight of the pEVA copolymer. In a particularly preferredembodiment, the polymer composition comprises polyalkyl(meth)acrylate(such as poly(n-butyl)methacrylate) with a molecular weight in the rangeof about 200 kD to about 500 kD and a pEVA copolymer with a vinylacetate content in the range of about 30% to about 34% by weight. Theconcentration of the bioactive agent in the polymeric coatingcomposition of this embodiment can be in the range of about 0.01% toabout 90% by weight, based upon the weight of the final coatingcomposition.

As used herein “weight average molecular weight” or M_(w), is anabsolute method of measuring molecular weight and is particularly usefulfor measuring the molecular weight of a polymer preparation. The weightaverage molecular weight (M_(w)) can be defined by the followingformula:

$M_{W} = \frac{\sum\limits_{:_{i}}^{\;}{N_{i}M_{i}^{2}}}{\sum\limits_{:_{i}}^{\;}{N_{i}M_{i}}}$wherein N represents the number of moles of a polymer in the sample witha mass of M, and Σ_(i) is the sum of all N_(i)M_(i) (species) in apreparation. The M_(w) can be measured using common techniques, such aslight scattering or ultracentrifugation. Discussion of M_(w) and otherterms used to define the molecular weight of polymer preparations can befound in, for example, Allcock, H. R. and Lampe, F. W., ContemporaryPolymer Chemistry; pg 271 (1990).

Coating compositions including aromatic poly(meth)acrylates can provideunexpected advantages in certain embodiments. Such advantages relate,for instance, to the ability to provide coatings having differentcharacteristics (such as different solubility characteristics) thanother coatings (for example, those that include apolyalkyl(meth)acrylate polymer), while maintaining a desiredcombination of other properties. Without intending to be bound by aparticular theory, it appears that the increased solubility(particularly in more polar solvents) that is provided by an aromatic,rather than an alkyl poly(meth)acrylate of this invention, permits theuse of poly(ethylene-co-vinyl acetate) polymers that are themselves morepolar (for example, having significantly greater vinyl acetateconcentrations) than those typically preferred for use with thepolyalkyl(meth)acrylates.

Examples of suitable aromatic poly(meth)acrylates includepolyaryl(meth)acrylates, polyaralkyl(meth)acrylates, andpolyaryloxyalkyl(meth)acrylates, in particular those with aryl groupshaving from six to sixteen carbon atoms and weight average molecularweights in the range of about 50 kD to about 900 kD. Preferred aromaticpoly(meth)acrylates include those compounds wherein at least one carbonchain and at least one aromatic ring are combined with acrylic groups(typically esters). For example, a polyaralkyl(meth)acrylate orpolyarylalkyl(meth)acrylate can be made from aromatic esters derivedfrom alcohols also containing aromatic moieties.

Examples of polyaryl(meth)acrylates includepoly-9-anthracenylmethacrylate, polychlorophenylacrylate,polymethacryloxy-2-hydroxybenzophenone, polymethacryloxybenzotriazole,polynaphthylacrylate, polynapthylmethacrylate,poly-4-nitrophenylacrylate, polypentachloroacrylate,polypentabromoacrylate, polypentafluoroacrylate,polypentachloromethacrylate, polypentabromomethacrylate,polypentafluoromethacrylate, polyphenylacrylate, andpolyphenylmethacrylate.

Examples of polyaralkyl(meth)acrylates include polybenzylacrylate,polybenzylmethacrylate, poly-2-phenethylacrylate,poly-2-phenethylmethacrylate, and poly-1-pyrenylmethylmethacrylate.

Examples of polyaryloxyalkyl(meth)acrylates includepolyphenoxyethylacrylate, polyphenoxyethylmethacrylate, andpolyethyleneglycolphenylether acrylates andpolyethyleneglycolphenylether methacrylates with varyingpolyethyleneglycol molecular weights.

The second polymer of the polymeric coating composition preferablyprovides one or more desirable properties, such as compatibility withthe first polymer and bioactive agent, hydrophobicity, durability,bioactive agent release characteristics, biocompatibility, moleculaiweight, and commercial availability, particularly when used in admixturewith the first polymer.

Examples of suitable second polymers are commercially available andinclude poly(ethylene-co-vinyl acetate) having vinyl acetateconcentrations in the range of about 10% to about 90% by weight of thepEVA copolymer, or in the range of about 20% to about 60% by weight ofthe pEVA copolymer, or in the range of about 30% to about 34% by weightof the pEVA copolymer. Poly(ethylene-co-vinyl acetate) co-polymershaving lower percent vinyl acetate can become increasingly insoluble intypical solvents, such as THF, toluene, and the like. The second polymercan be obtained commercially in the form of beads, pellets, granules,and the like.

A particularly preferred coating composition in accordance with theinvention comprises polyalkyl(meth)acrylates (for example,poly(n-butyl)methacrylate) or aromatic poly(meth)acrylates (for example,polybenzyl(meth)acrylates) and poly(ethylene-co-vinyl acetate)copolymers. This particular composition has proven useful with absolutepolymer concentrations (as defined herein) in the range of about 0.05%to about 70% by weight of the total coating composition, more preferablyin the range of about 0.25% to about 10% by weight of the total coatingcomposition.

In one preferred embodiment, the polymer composition includes a firstpolymer with a weight average molecular weight in the range of about 100kD to about 500 kD, and a pEVA copolymer with a vinyl acetate content inthe range of about 10% to about 90% by weight, and more preferably inthe range of about 20% to about 60% by weight. In a particularlypreferred embodiment, the polymer composition includes a first polymerwith a weight average molecular weight in the range of about 200 kD toabout 500 kD, and a pEVA copolymer with a vinyl acetate content in therange of about 30% to about 34% by weight.

In preferred embodiments, the coating composition comprises a bioactiveagent. For purposes of the description herein, reference will be made to“bioactive agent,” but it is understood that the use of the singularterm does not limit the application of bioactive agents contemplated,and any number of bioactive agents can be provided using the teachingherein. As used herein, “bioactive agent” refers to an agent thataffects physiology of biological tissue. Bioactive agents usefulaccording to the invention include virtually any substance that possessdesirable therapeutic characteristics for application to theimplantation site.

Exemplary bioactive agents include, but are not limited to, thrombininhibitors; antithrombogenic agents; thrombolytic agents; fibrinolyticagents; vasospasm inhibitors; calcium channel blockers; vasodilators;antihypertensive agents; antimicrobial agents, such as antibiotics (suchas tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin,gramicidin, cephalexin, oxytetracycline, chloramphenicol, rifampicin,ciprofloxacin, tobramycin, gentamycin, erythromycin, penicillin,sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole,sulfisoxazole, nitrofurazone, sodium propionate), antifungals (such asamphotericin B and miconazole), and antivirals (such as idoxuridinetrifluorothymidine, acyclovir, gancyclovir, interferon); inhibitors ofsurface glycoprotein receptors; antiplatelet agents; antimitotics;microtubule inhibitors; anti-secretory agents; active inhibitors;remodeling inhibitors; antisense nucleotides; anti-metabolites;antiproliferatives (including antiangiogenesis agents); anticancerchemotherapeutic agents; anti-inflammatories (such as hydrocortisone,hydrocortisone acetate, dexamethasone 21-phosphate, fluocinolone,medrysone, methylprednisolone, prednisolone 21-phosphate, prednisoloneacetate, fluoromethalone, betamethasone, triamcinolone, triamcinoloneacetonide); non-steroidal anti-inflammatories (such as salicylate,indomethacin, ibuprofen, diclofenac, flurbiprofen, piroxicam);antiallergenics (such as sodium chromoglycate, antazoline,methapyriline, chlorpheniramine, cetrizine, pyrilamine,prophenpyridamine); anti-proliferative agents (such as 13-cis retinoicacid); decongestants (such as phenylephrine, naphazoline,tetrahydrazoline); miotics and anti-cholinesterase (such as pilocarpine,salicylate, carbachol, acetylcholine chloride, physostigmine, eserine,diisopropyl fluorophosphate, phospholine iodine, demecarium bromide);mydriatics (such as atropinsurface, cyclopentolate, homatropine,scopolamine, tropicamide, eucatropine, hydroxyamphetamine);sympathomimetics (such as epinephrine); antineoplastics (such ascarmustine, cisplatin, fluorouracil); immunological drugs (such asvaccines and immune stimulants); hormonal agents (such as estrogens,estradiol, progestational, progesterone, insulin, calcitonin,parathyroid hormone, peptide and vasopressin hypothalamus releasingfactor); beta adrenergic blockers (such as timolol maleate, levobunololHCl, betaxolol HCl); immunosuppressive agents, growth hormoneantagonists, growth factors (such as epidermal growth factor, fibroblastgrowth factor, platelet derived growth factor, transforming growthfactor beta, somatotropin, fibronectin); carbonic anhydrase inhibitors(such as dichlorophenamide, acetazolamide, methazolamide); inhibitors ofangiogenesis (such as angiostatin, anecortave acetate, thrombospondin,anti-VEGF antibody); dopamine agonists; radiotherapeutic agents;peptides; proteins; enzymes; extracellular matrix components; ACEinhibitors; free radical scavengers; chelators; antioxidants;anti-polymerases; photodynamic therapy agents; gene therapy agents; andother therapeutic agents such as prostaglandins, antiprostaglandins,prostaglandin precursors, and the like.

The particular bioactive agent, or combination of bioactive agents, canbe selected depending upon one or more of the following factors: theapplication of the controlled delivery device, the medical condition tobe treated, the anticipated duration of treatment, characteristics ofthe implantation site, the number and type of bioactive agents to beutilized, and the like.

The concentration of the bioactive agent in the coating composition canbe provided in the range of about 0.01% to about 90% by weight, based onthe weight of the final coating composition. Preferably, the bioactiveactive agent is present in the coating composition in an amount in therange of about 75% by weight or less, preferably about 50% by weight orless. The amount of bioactive agent in the coating composition can be inthe range of about 1 μg to about 10 mg, or about 100 μg to about 1500μg, or about 300 μg to about 1000 μg.

The coating composition can be applied to the controlled delivery deviceusing any suitable methods. For example, the coating composition can beapplied by dipping, spraying, and other common methods for applyingcoating compositions to implantable devices. The suitability of thecoating composition for use on a particular material, and in turn, thesuitability of the coated composition, can be evaluated by those skilledin the art, given the present description.

In some aspects, the coating composition can be applied to thecontrolled delivery device utilizing an ultrasonic spray head asdescribed in Example 2. As described in Example 2, the cap of thecontrolled delivery device can be supported with a pin vice during thecoating procedure.

In some embodiments, the surface of the body member can be pretreatedprior to provision of the coating composition. Any suitable surfacepretreatment commonly employed in coating implantable devices can beutilized in accordance with the invention, including, for example,treatment with silane, polyurethane, parylene, and the like. Forexample, Parylene C (commercially available from Union CarbideCorporation), one of the three primary variants of parylene, can be usedto create a polymer layer on the surface of a medical device. Parylene Cis a para-xylylene containing a substituted chlorine atom, which can becoated by delivering it in a vacuum environment at low pressure as agaseous polymerizable monomer. The monomer condenses and polymerizes onsubstrates at room temperature, forming a matrix on the surface of themedical device. The coating thickness can be controlled by pressure,temperature, and the amount of monomer used. The parylene coatingprovides an inert, non-reactive barrier.

In some embodiments, the coated composition comprises at least twolayers, wherein each layer comprises the same coated composition, ordifferent coated compositions. In one such embodiment, a first layerhaving either bioactive agent alone, or bioactive agent(s) together withone or more of the polymers (first polymer and/or second polymer) isapplied, after which one or more additional layers are applied, eachwith or without bioactive agent. These different layers, in turn, cancooperate in the resultant composite coating to provide an overallrelease profile having certain desired characteristics, and isparticularly preferred for use with bioactive agents having highmolecular weight. According to the invention, the composition ofindividual layers of the coating can include any one or more of thefollowing: one or more bioactive agents, the first polymer, and/or thesecond polymer, as desired.

Preferably, the coating composition is applied to the body member of thecontrolled delivery device surface in one or more applications. Themethod of applying the coating composition to the body member istypically governed by such factors as the geometry of the device andother process considerations. The coated composition can be subsequentlydried by evaporation of the solvent. The drying process can be performedat any suitable temperature, (for example, room temperature or elevatedtemperature), and optionally with the assistance of vacuum.

In some preferred embodiments, the coating composition is applied to thebody member under conditions of controlled relative humidity. As usedherein, “relative humidity” is the ratio of the water vapor pressure (orwater vapor content) to the saturation vapor pressure (or the maximumvapor content) at a given temperature of the air. The saturation vaporpressure in the air varies with air temperature: the higher thetemperature, the more water vapor it can hold. When saturated, therelative humidity in the air is 100% relative humidity. According tosome embodiments of the invention, the coating composition can beapplied to the body member under conditions of increased or decreasedrelative humidity as compared to ambient humidity.

According to the invention, humidity can be controlled in any suitablemanner, including at the time of preparing and/or applying the coatingcomposition to the body member. For example, when humidity is controlledat the time of preparing the coating composition, the water content ofthe coating composition can be adjusted, before and/or after the coatingcomposition is applied to the body member. When humidity is controlledat the time of applying the coating composition, the coating compositioncan be applied to the body member in a confined chamber or area adaptedto provide a relative humidity that differs from ambient humidity.Generally, it has been found that applying coating compositions underconditions of increased humidity will typically accelerate release ofthe bioactive agent, while applying coating compositions underconditions of decreasing humidity levels will tend to decelerate releaseof the bioactive agent. As contemplated in the invention, even ambienthumidity can be considered “controlled” humidity if it has beencorrelated with and determined to provide a corresponding controlledrelease of the bioactive agent.

Moreover, and particularly when coating a plurality of coatingcompositions onto the body member of the controlled delivery device toprovide the final coated composition, humidity can be controlled indifferent ways (for example, using a controlled environment as comparedto adjusting the water content of the coating composition) and/or atdifferent levels to provide a desired release profile for the resultingcoated composition. As described previously, a coated composition can beprovided using a plurality of individual steps or layers of coatingcomposition, including, for instance, an initial layer having onlybioactive agent (or bioactive agent with one or both polymers), overwhich is coated one or more additional layers containing suitablecombinations of bioactive agent, first polymer, and/or second polymer,the combined result of which is to provide a coated composition of theinvention.

Thus, in preferred embodiments, the invention provides the ability toreproducibly control the release of a bioactive agent from a controlleddelivery device.

In some embodiments, a plurality of coating compositions andcorresponding coating steps can be employed, each with its owncontrolled humidity (when desired), in order to provide a desiredcombination of layers, each with its corresponding release profile.Those skilled in the art will appreciate the manner in which thecombined effect of these various layers can be used and optimized toachieve various effects in vivo.

In yet another embodiment, the desired release rate of the bioactiveagent from the coated composition can be selected by applying thecoating composition to surfaces at a plurality of different humiditylevels, and evaluating the corresponding release profiles to determine acontrolled humidity level corresponding to a desired profile. In onesuch embodiment, for instance, the coating composition is applied to thedevice under relative humidity controlled at a level in the range ofabout 0% to about 95% relative humidity (at a given temperature, in therange of about 15° C. to about 30° C.), and more preferably in the rangeof about 0% to about 50% relative humidity. Without intending to bebound by a particular theory, it has been found that potentialdifferences in the ambient humidity, as between coating runs at the samelocation, and/or as between different coating locations, can varysignificantly, and in a manner that might affect such properties as therelease of the bioactive agent. By using a controlled humidity, theinvention can provide a coated composition that displays significantlymore controllable and reproducible release characteristics.

The coating composition of the invention can be provided in any suitableform, for example, in the form of a true solution, or fluid orpaste-like emulsion, mixture, dispersion, or blend. In turn, the coatedcomposition will generally result from the removal of solvents or othervolatile components and/or other physical-chemical actions (for example,heating or illumination) affecting the coated composition in situ uponthe controlled delivery device surface.

The overall weight of the coated composition upon the surface of thecontrolled delivery device is typically not critical. The weight of thecoated composition attributable to the bioactive agent can be in therange of about 1 μg to about 10 mg of bioactive agent per cm² of thesurface area of the controlled delivery device. In some embodiments, thesurface area can comprise all or a portion of the body member 2 of thedevice. In alternative embodiments, the surface area can comprise thebody member 2 and the cap 8 of the device. Preferably, the weight of thecoated composition attributable to the bioactive agent is in the rangeof about 0.01 mg to about 10 mg of bioactive agent per cm² of thesurface area of the controlled delivery device. This quantity ofbioactive agent is generally effective to provide adequate therapeuticeffect under physiological conditions. As used herein, the surface areais the macroscopic surface area of the device.

In preferred embodiments, the final coating thickness of the coatedcomposition on the controlled delivery device will typically be in therange of about 0.1 μm to about 100 μm, or in the range of about 5 μm toabout 60 μm. This level of coating thickness is generally effective toprovide a therapeutically effective amount of bioactive agent to theimplantation site under physiological conditions. The final coatingthickness can be varied, and at times be outside the preferred rangesidentified herein, depending upon such factors as the total amount ofbioactive agent to be included in the coated composition, the type ofbioactive agent, the number of bioactive agents to be included, thetreatment course, the implantation site, and the like.

Thickness of the coated composition on the controlled delivery devicecan be assessed using any suitable techniques. For example, portions ofthe coated composition can be delaminated by freezing the coatedcontrolled delivery device, for example, utilizing liquid nitrogen. Thethickness at the edge of a delaminated portion can then be measured byoptical microscopy. Other visualization techniques known in the art canalso be utilized, such as microscopy techniques suitable forvisualization of coatings having the thickness described herein of theinvention.

In preferred embodiments, the controlled delivery device is sterilizedutilizing common sterilization techniques, prior to implantation intothe body. Sterilization can be accomplished, for example, utilizingethylene oxide or gamma sterilization, as desired. In preferredembodiments, sterilization techniques utilized do not affect thepolymeric coated composition (for example, by affecting release of thebioactive agent, stability of the coating, and the like).

According to the invention, the controlled delivery device preferablyprovides the ability to deliver one or more bioactive agents in acontrolled release manner. As used herein, “controlled release” refersto release of a compound (for example, a bioactive agent) into apatient's body at a desired dosage (including dosage rate and totaldosage) and duration of treatment. For example, the particularcomposition of the coating composition (including the amounts and ratiosof the individual components of the coating composition) can be modifiedto achieve a desired release profile (amount of bioactive agent releasedfrom the coating composition per unit time) of the bioactive agent.While not intending to be bound by one particular theory, the releasekinetics of the bioactive agent in vivo are thought to generally includeboth a short term (“burst”) release component, within the order ofminutes to hours or less after implantation of the device, and a longerterm release component, which can range from on the order of hours todays or even months of useful release. As used herein, the accelerationor deceleration of bioactive agent release can include either or both ofthese release kinetics components.

The desired release profile of the bioactive agent can depend upon suchfactors as the particular bioactive agent selected, the number ofindividual bioactive agents to be provided to the implantation site, thetherapeutic effect to be achieved, the duration of the implant in thebody, and other factors known to those skilled in the art.

The ability to provide controlled release of a bioactive agent at animplantation site can provide many advantages. For example, thecontrolled delivery device can be maintained at an implantation site forany desired amount of time, and the release kinetics of the bioactiveagent can be adjusted to deliver the total amount of bioactive agent, atthe desired rate, to achieve a desired therapeutic effect. In someembodiments, the ability to provide controlled release of bioactiveagent at the implantation site allows implantation of only one device,which can be maintained in place until the desired therapeutic effect isachieved, without need to remove the device and replace the device witha new supply of bioactive agent. Preferably, some embodiments of theinvention avoid the need to refill a reservoir of bioactive agent at theimplantation site. In some embodiments, the controlled delivery devicecan avoid the need for systemic application of bioactive agents, whichcan harm other tissues of the body.

The controlled delivery device can be utilized to deliver any desiredbioactive agent or combination of bioactive agents to the eye, such asthe bioactive agents described herein. The amount of bioactive agent(s)delivered over time is preferably within the therapeutic level, andbelow the toxic level. For example, a preferred target dosage fortriamcinolone acetonide for use in treating diseases or disorders of theeye is preferably in the range of about 0.5 μg/day to about 2 μg perday. Preferably, the treatment course is greater than 6 months, morepreferably greater than one year. Thus, in preferred embodiments, thebioactive agent is released from the coated composition in atherapeutically effective amount for a period of 6 months or more, or 9months or more, or 12 months or more, or 36 months or more, whenimplanted in a patient.

Preferred embodiments of the invention provide a controlled deliverydevice that can release bioactive agent at a constant rate over extendedperiods of time. Moreover, the controlled delivery device preferablyprovides the ability to control the rate of release of bioactive agentby altering the formulation of the coating composition (for example, byproviding the first polymer and second polymer in different relativeamounts, and/or by altering the amount of bioactive agent included inthe coating composition). As illustrated in the Examples, preferredcoated compositions can provide release of a bioactive agent in areproducible manner, for varying time periods, over a range of releaserates. In the Examples, coating compositions having varying amounts ofpoly(ethylene-co-vinyl acetate) relative to the amount ofpoly(n-butyl)methacrylate, and a constant amount of a bioactive agent,were prepared and coated onto stainless steel substrates. The releaserates of bioactive agent from the coated composition were determined inPBS utilizing the Elution Assay described herein. Results illustratedthat the bioactive agent could be released from the coated compositionfor surprisingly long periods of time in vitro. Moreover, the coatingcompositions could be formulated to provide substantially linear releaserates. Based upon the observed release rates in vitro, it is expectedthat in vivo release rates will be higher than those in PBS. See Jaffeet al., supra. Differences in release rates were observed among thecoated compositions, which relate to differences in polymer compositionof the coated compositions. Thus, in preferred embodiments, the polymercomposition of the coating compositions can be manipulated to controlthe release rate of the bioactive agent.

Use of the controlled delivery device can be further understood from thefollowing discussion relating to a method for controlled release of abioactive agent to the eye and with reference to FIGS. 5 and 6. However,it will be understood that the principles described below can be appliedto any implantation site within a patient's body.

In accordance with the invention, the controlled delivery device isfabricated, utilizing the teaching herein, in preparation for thesurgical procedure. An incision in the body is made to provide access tothe implantation site. For example, when used to deliver bioactive agentto the eye, a sclerotomy is created for insertion of the controlleddelivery device. Conventional techniques can be used for the creation ofthe sclerotomy. Such techniques include the dissection of theconjunctiva 32 and the creation of pars plana scleral incisions throughthe sclera 28. As shown in FIGS. 5 and 6, the dissection of theconjunctiva 32 typically involves pulling back the conjunctiva 32 aboutthe eye so as to expose large areas of the sclera 28, and the clippingor securing of the conjunctiva 32 in that pulled back state (the normalposition of the conjunctiva is shown in phantom). In other words, thesclera 28 is exposed only in the areas where the pars plana scleralincisions are to be made. Surgical instruments used in the procedure arethen passed through these incisions. Thus, the incisions should be madelarge enough to accommodate the instruments required for the procedure.

Alternatively, the creation of the sclerotomy can be accomplished by useof an alignment device and method, such as that described in U.S. patentapplication Ser. No. 09/523,767, that enables sutureless surgicalmethods and devices thereof. In particular, such methods and devices donot require the use of sutures to seal the openings through whichinstruments are inserted. The alignment devices are inserted through theconjunctiva and sclera to form one or more entry apertures. Preferably,the alignment devices are metal or polyimide cannulas through which thesurgical instruments used in the procedure are inserted into the eye.

In further embodiments, the device can be implanted directly through aself-starting transconjunctival trans-scleral “needle stick.” Forexample, the body member 2 of the device can include a sharp tip 10,such as that illustrated in FIG. 3. According to this embodiment, thesharp tip 10 can be utilized to pierce the body and thereby create theincision site and access to the implantation site. In this case, noconjunctival surgery or extraneous alignment device is necessary.

In further embodiments, the conjunctival tissue can be dissected toexpose a portion of the pars plana region, and a needlestick can be madeinto the sclera in the exposed region. A self-starting coil thatincludes a sharp tip is then inserted through the pars plana at the siteof the needlestick, and the coil is rotated through the sclera until thecap of the device abuts the sclera. In some preferred embodiments, theneedlestick is smaller than the diameter of the material forming thebody member of the implantable device (for example, a 30-gaugeneedlestick can be used with an implantable device having a body memberfabricated of a material with a diameter of 0.5 mm or less). Theconjunctival tissue is then pulled over the cap, to provide a flap or“seal” over the device, thus minimizing irritation of the implantationsite, foreign body sensation, and the like. Optionally, the conjunctivaltissue can be further secured by a single suture (in preferredembodiments, a biodegradable suture).

In some embodiments, it can be preferable to create an incision sitethat is slightly larger than the dimensions of the proximal portion ofthe body member. For example, when the device includes a cap 8 and isimplanted into the eye, it can be preferable to create an incision thatis larger than the largest diameter of the cap 8, such that the cap sitsbelow the outer surface of the sclera. For example, a partial incisionin the sclera can be made to create a scleral flap. Once the device hasbeen implanted, and the cap 8 is placed so that it abuts the incisionsite, the scleral flap can be folded back over the device, thusproviding a covering over the cap. Alternatively, when the proximal endof the body member does not include a cap 8, a flap-like cover can stillbe utilized to cover the proximal end of the device, in accordance withthe description above. Preferably, these embodiments minimize thecontact of the proximal end (for example, the cap 8) of the device withother body tissues, thereby reducing such risks as irritation of bodytissues, and/or translation of movement of the eye to the device,thereby potentially damaging eye tissues. This can provide one or moreadvantages, such as reduced tendency for movement of the eye to betranslated to the controlled delivery device, since the proximal end ofthe device will not be sitting at the surface of the eye and thus incontact with other body tissues; and reduced irritation of surroundingtissues.

The body member 2 is then inserted into the eye. For example, inembodiments wherein the body member 2 has a coil shape, the body member2 is inserted into the eye by rotating or twisting the body member 2into the eye until the cap 8 abuts the outer surface of the eye. Inembodiments wherein the body member 2 is fabricated of a shape memorymaterial, the shape memory material is first cooled to a temperature atwhich the martensite phase is stable and the device is deformed, forexample, into a linear shape. The device is then inserted into the eye.To return the device to its memory shape, the device is leftunrestrained and is simply allowed to reach a temperature (for example,by heating the device) above the martensite phase temperature. Forexample, the shape memory material can be heated by a laser to returnthe device to a temperature above the martensite phase temperature. Theshape memory material can also be selected such that the martensitephase temperature is below body temperature so that the material issimply cooled to below body temperature, deformed to a linear shape, andinserted into the eye. Then, as the material warms up within the eye tobody temperature, the device can return to its remembered shape. Asdiscussed herein, when laser application is utilized, conditions arepreferably controlled to maintain such parameters as wavelength andtemperature, to minimize adverse effect on the polymeric coatedcomposition.

FIG. 5 illustrates a controlled delivery device according to oneembodiment of the invention that is implanted in the eye. When implantedinto the eye, it is desirable to limit the length L of controlleddelivery devices to prevent the controlled delivery device from enteringthe central visual field A (see FIG. 6). If the implant enters thecentral visual field A, this can result in blind spots in the patient'svision and can increase the risk of damage to the retinal tissue andlens capsule. Thus, for example, when the controlled delivery device isinserted at the pars plana (as shown in FIG. 5), the distance from theimplantation site on the pars plana to the central visual field A ispreferably less than about 1 cm.

Optionally, after the device is implanted into the eye, the cap 8 canthen be sutured or otherwise secured to the sclera to maintain thecontrolled delivery device in place. In preferred embodiments, nofurther manipulation of the device is required for delivery of one ormore bioactive agents to the interior of the eye. The conjunctiva can beadjusted to cover the cap 8 of the device, when desired, and thesurgical procedure is completed.

In other embodiments, when a lumen is included in the device fordelivery of one or more additional substances to the interior of theeye, further steps can be included as follows. If a cover is used toclose the port(s), it is removed at this time, and if used, a collar forproviding a snug fit about the injection mechanism (such as a syringe)is provided. The injection mechanism is then connected with the port(s)for injection of one or more substances to the controlled deliverydevice. If the port(s) are composed of an self-sealing material throughwhich the needle of an injection mechanism can be inserted and whichseals off automatically when the injection mechanism is removed, theinjection mechanism is simply inserted through the port and thesubstance injected. Following injection, the conjunctiva can be adjustedto cover the cap 8 of the device, if desired.

The controlled delivery device of the invention can be used to deliverone or more bioactive agents to the eye for the treatment of a varietyof ocular conditions such as, for example, retinal detachment;occlusions; proliferative retinopathy; proliferative vitreoretinopathy;diabetic retinopathy; inflammations such as uveitis, choroiditis, andretinitis; degenerative disease (such as age-related maculardegeneration, also referred to as ANM); vascular diseases; and varioustumors including neoplasms. In yet further embodiments, the controlleddelivery device can be used post-operatively, for example, as atreatment to reduce or avoid potential complications that can arise fromocular surgery. In one such embodiment, the controlled delivery devicecan be provided to a patient after cataract surgical procedures, toassist in managing (for example, reducing or avoiding) post-operativeinflammation.

In some applications, additives can further be included with thebioactive agent and/or additional substance to be delivered to theimplantation site. Examples of suitable additives include, but are notlimited to, water, saline, dextrose, carriers, preservatives,stabilizing agents, wetting agents, emulsifying agents, excipients, andthe like.

Once the bioactive agent has been delivered to the implantation site,the controlled delivery device can be removed if the requiredtherapeutically effective amount of bioactive agent has been deliveredfor treatment of the condition.

The following examples illustrate the present invention without,however, limiting the same thereto.

EXAMPLES

Test Methods

The suitability of particular coated compositions for in vivo use can bedetermined by one or more of a variety of methods, including theDurability Test and Elution Assay. Examples of each test are describedherein.

Sample Preparation

One-millimeter diameter stainless steel wires (for example, 316 L grade)were cut into 2-centimeter lengths. The wire segments were treated witha Parylene C coating composition (Union Carbide Corporation), asdescribed herein. The wire segments were weighed on a micro-balance.

Coating compositions were prepared at a range of concentrations in anappropriate solvent, in the manner described herein. The coatingmixtures were applied to respective wires, or portions thereof, bydipping or spraying, and the coated wires were allowed to dry by solventevaporation. The coated wires were then re-weighed. From this weight,the mass of the coatings was calculated, which in turn permitted themass of the coated polymer(s) and bioactive agent(s) to be determined.

The durability of the coated composition was determined in the followingmanner.

Durability Test

The Durability Test utilized was as follows. Coated devices wereprepared as described above. The coated devices were mounted to aninsertion tool that firmly engages the cap of the device while avoidingmechanical contact with the coated portion of the device. The devicesincluded a distal sharp tip that was utilized to pass through theconjunctiva and sclera and into the interior of the eye. Cadavericporcine eyes were obtained, and the distal sharp tip was utilized toplace the devices into the eye until the cap of the device was flushwith the sclera.

After implantation, the coated devices were immediately removed,utilizing the insertion device used for implantation. Devices werecarefully cleaned without the use of solvents (deionized water was usedto remove any tissue adhering to the device surface). The devices werethen analyzed for surface coating defects (such as delamination of thecoating) under light microscopy.

Elution Assay

Any suitable Elution Assay can be used to determine the extent and/orrate of bioactive agent release from the coated composition underphysiological conditions. In general, it is desirable that less than 50%of the total quantity of the drug to be released is released in thefirst 24 hours after introduction into physiological conditions. It isfrequently desirable for quantities of bioactive agent to be releasedfor a duration of at least 30 days. After all of the bioactive agent hasbeen released, SEM evaluation should reveal an intact coating.

The Elution Assay utilized herein was as follows. Phosphate bufferedsaline (PBS, 10 mM phosphate, 150 mM NaCl, pH 7.4, aqueous solution) waspipetted in an amount of 3 ml to 10 ml into an amber vial with a Teflon™lined cap. A wire or coil treated with the coating composition wasimmersed into the PBS. A stir bar was placed into the vial and the capwas screwed tightly onto the vial. The PBS was stirred with the use of astir plate, and the temperature of the PBS was maintained at 37° C. withthe use of a water bath. The sampling times were chosen based upon theexpected or desired elution rate. At the sampling time point, the wireor coil was removed from the vial and placed into a new vial containingfresh PBS. A UV/V is spectrophotometer was used to determine theconcentration of the drug in the PBS solution that previously containedthe wire or coil treated with the coating composition. The cumulativeamount of drug eluted versus time was plotted to obtain an elutionprofile.

At the conclusion of the Elution Assay, the wire or coil was washed withwater, dried and re-weighed. Correlation between the percent bioactiveagent eluted and the percent weight loss of the coated composition wasverified.

When desired, the coating can also be evaluated by measuring the coatingthickness (for example, using a Minitest 4100 thickness gauge), and thecoating quality (such as roughness, smoothness, evenness, and the like)can be analyzed by SEM analysis.

Nomenclature

The following abbreviations are used in the examples:

pEVA poly(ethylene-co-vinyl acetate) (SurModics, Inc., Eden Prairie, MN)PBMA poly(n-butyl)methacrylate (SurModics, Inc., Eden Prairie, MN) TAtriamcinolone acetonide (Sigma-Aldrich Chemical, St. Louis, MO)

In the following examples, the compositional details of each coatingcomposition are summarized as a ratio of the weight percentages ofpolymers used to create the coating composition. For example, a coatingcomposition designated TA/pEVA/PBMA (50/49/1) is made by providing, on arelative basis, 50 parts by weight triamcinolone acetonide, 49 parts byweight poly(ethylene-co-vinyl acetate), and 1 part by weight ofpoly(n-butyl)methacrylate.

Example 1 Release of Triamcinolone Acetonide from Stainless Steel Wires

Three different polymer solutions were prepared in tetrahydrofuran (THF)in the manner provided below in order to provide coating compositions inthe form of a one-part system. The three solutions contained varyingamounts of poly(ethylene-co-vinyl acetate), with a vinyl acetate contentof 33%(w/w), relative to the amount of poly(n-butyl)methacrylate, withan approximate weight average molecular weight of 337 kD. Each of thethree solutions contained a constant amount of triamcinolone acetoniderelative to the total polymer weight.

The coating compositions were prepared as follows. The polymers wereinitially added to the THF and dissolved overnight while mixing on ashaker at 200 revolutions per minute (rpm) at room temperature(approximately 20° C. to 22° C.). After dissolution of the polymer, thetriamcinolone acetonide was added, and the mixture was placed back onthe shaker at 100 rpm for 1 hour, to form the one-part coatingcomposition. The compositions prepared are summarized below in Table I:

TABLE I Coating Compositions applied to wire surfaces. Parts by weightWeight of Coating Coating Composition (pbw) Composition (μg) Coating 1aTA/pEVA/PBMA 50/49/1  1222 Coating 1b TA/pEVA/PBMA 50/36/14 1266 Coating1c TA/pEVA/PBMA 50/15/35 1204

Stainless steel wire samples were prepared for coating as follows. Thestainless steel wire was cleaned by soaking in a 6% (by volume) solutionof ENPREP-160SE (Cat. # 2108-100, Enthone-OMI, Inc., West Haven, Conn.)in deionized water for 1 hour. After soaking, the parts were then rinsedseveral times with deionized water. After rinsing, the stainless steelwire was soaked for 1 hour at room temperature in 0.5% (by volume)methacryloxypropyltrimethoxy silane (Cat.# M6514, Sigma Aldrich, St.Louis, Mo.) made in a 50% (by volume) solution of deionized water andisopropyl alcohol. The stainless steel wires were allowed to drain andair dry. The dried wires were then placed in a 100° C. oven for 1 hour.

After oven-drying, the stainless steel wires were placed in a parylenecoating reactor (PDS 2010 LABCOTER™ 2, Specialty Coating Systems,Indianapolis, Ind.) and coated with 2 g of Parylene C (Specialty CoatingSystems, Indianapolis, Ind.) by following the operating instructions forthe LABCOTER™ system. The resulting Parylene C coating was approximately1-2 μm thickness.

Solutions for Coatings 1a, 1b, and 1c were sprayed onto the Parylene Ctreated wires using an IVEK sprayer (IVEK Dispenser 2000, IVEK Corp.,North Springfield, VT) mounting a nozzle with a 1.0 mm (0.04 inch)diameter orifice and pressurized at 421.84 g/cm² (6 psi). The distancefrom the nozzle to the wire surface during coating application was 5 to5.5 cm. A coating application consisted of spraying 40 μl of the coatingsolution back and forth on the wire for 7 seconds. The spraying processof the coating was repeated until the amount of TA on the wire equaledthe amount of TA listed for Coatings 1a, 1b, and 1c seen in FIG. 7. Thecoating compositions on the wire were dried by evaporation of solvent,approximately 8-10hours, at room temperature (approximately 20° C. to22° C.). After drying, the coated wires were re-weighed. From thisweight, the mass of the coating was calculated, which in turn permittedthe mass of the coated polymer(s) and bioactive agent to be determined.

The coated wires were then subjected to the Elution Assay describedabove. Results of the Elution Assay for each coating composition areillustrated in FIG 7.

The release rates of the coatings were determined for greater than 175days. For Coating 1c, the calculated release rate was 0.5 μg/day betweendays 51 and 456, and the release rate was linear over the duration ofthe experiment. For Coating 1a, the calculated release rate was 4.2μg/day between days 14 and 79, and for Coating 1b, the calculated linearrelease rate was 1.2 μg/day between days 84 and 337. Utilizing theserelease rates, it was calculated that Coating 1c would be released fromthe coated composition into PBS (assuming 100% release of TA) for aperiod exceeding 3 years.

As shown in FIG. 7, Coating 1a included an initial loading of 611 μg ofTA, and 600 μg of the bioactive agent was released within 190 days.Coating 1b included an initial loading of 633 μg of TA, and 631 μg ofthe bioactive agent was released within 372 days. Coating 1c included aninitial loading of 602 μg of TA, and 240 μg of the bioactive agent wasreleased within 456 days.

Results indicate that a bioactive agent, in this case, triamcinoloneacetonide, was predicted to elute from a coated composition according tothe invention for surprisingly long periods of time in vitro (over threeyears). Further, the coating composition can provide a substantiallylinear release rate over time. Moreover, as the results indicate, thecoated composition can be varied, for example, by varying the weightratio of the first polymer and second polymer, to control the elutionrate of a bioactive agent, such as triamcinolone acetonide, as desired.Thus, a treatment course can be identified by an interventionalist, andthe polymeric coating composition according to the invention can beformulated to provide a controlled release profile to achieve thedesignated treatment course. As described in more detail herein, therelease profile can be further controlled by controlling humidityconditions of the coating composition.

At the conclusion of the Elution Assay, the wire was washed with water,dried and re-weighed. Pre- and post-elution data for coated compositions1a and 1b are provided in Table II below:

TABLE II Elution Data for Coated Compositions 1a and 1b. % released asshown by Coated coil Coated coil Drug Drug coil weight % released weightbefore weight after released initial loss during as indicated Coatingelution (mg) elution (mg) (μg) (μg) elution by UV spec. 1a 25.775 25.183592 611 97 98 1b 30.187 29.567 620 633 98 105As shown in the results, the amount of drug released correlated wellwith the initial drug weight in the coated composition and with thepercent released as indicated by the Elution Assay.

Example 2 In Vitro Release of Triamcinolone Acetonide from Helical Coils

Two different solutions were prepared in tetrahydrofuran (THF) as inExample 1. The compositions prepared are summarized in Table III:

TABLE III Coating Compositions applied to the Helical Coil. Parts byweight Weight of coated Coating Composition (pbw) composition (μg)Coating 1d TA/pEVA/pBMA 50/27.5/22.5 1950 Coating 1e TA/pEVA/pBMA50/40/10 1928

Helical coils with attached caps were fabricated from the alloy MP35N™(commercially available from ESPI, Ashland, Oreg.). The coils werecleaned in an alkaline solution, then rinsed with deionized water. Thecoils underwent additional cleaning using an isopropyl alcohol wash andrinse. The coils were dried and weighed prior to coating.

Solutions for Coatings 1d and 1e were sprayed onto the coils usingultrasonic coater equipment that consisted of an ultrasonic spray head(Sono-Tek Milton, N.Y.) and syringe pump system for the coatingsolution. A pin vise was used to hold the cap of the coil and the coilwas held perpendicular to the spray head and rotated. The spray head wasmoved over the coil to apply the coating composition. The sprayingprocess was continued until the amount of TA on the coils equaled theamount of TA listed for Coatings 1d and 1e listed in Table III. Thecoating compositions on the helical coil were dried by evaporation ofsolvent at room temperature (approximately 20° C. to 22° C.). Afterdrying, the coated coils were re-weighed. From this weight, the mass ofthe coating was calculated, which in turn permitted the mass of thecoated polymer(s) and bioactive agent to be determined.

The coated coils were then subjected to the Elution Assay describedabove. Results of the Elution Assay for each coating composition areillustrated in FIG. 8.

The release of TA was monitored over 63 days. As shown in FIG. 8,Coating 1d included an initial drug load of 975 μg of TA andapproximately 171 μg of the bioactive agent was released within 63 days.Coating 1e included an initial drug load of 914 μg of TA andapproximately 371 μg of the bioactive agent was released within 63 days.For coating 1d, the calculated release rate was 1.6 μg/day between days20 and 63. For coating 1e, the calculated release rate was 3.6 μg/daybetween days 20 and 63.

Similar to the results discussed in Example I, the elution data forCoatings 1d and 1e indicate that a bioactive agent can be predicted toelute from a coated composition according to the invention forsurprisingly long periods of time in vitro. Further, the coatingcompositions again showed a substantially linear release rate over time(between days 20 and 63). Similar to Example I, results illustrated thatthe elution rate of the bioactive agent can be controlled by varying thecoated composition.

At the conclusion of the Elution Assay, the coils were washed withwater, dried, and reweighed. Pre- and post-elution data for coatedcomposition 1d and 1e along with the percent released as indicated bythe Elution Assay is provided in Table IV below:

TABLE IV Elution Data for Coated Compositions 1d and 1e. % released asshown by Coated coil Coated coil Drug Drug coil weight % released weightbefore weight after released initial loss during as indicated Coatingelution (mg) elution (mg) (μg) (μg) elution by UV spec. 1d 32.392 32.213179 975 19 18 1e 33.204 32.817 387 913.5 42 41As shown in the results, the percent of drug released as determined bythe coil weight before and after elution correlated well with thepercent of drug released as determined by UV spectroscopy.

Example 3 In Vivo Release of Triamcinolone Acetonide from Helical Coils

Ten coils were coated with two different formulations, Dose A and DoseB, and were implanted into the vitreous chamber of rabbit eyes toprovide sustained release of triamcinolone acetonide. Table V summarizesthe coating compositions applied to the coils in this Example. Dose Bwas designated a “fast release” coating, and this coating compositionincluded a relatively larger ratio of pEVA to PBMA, as compared to the“slow release” Dose A coating composition.

The coating solutions were prepared according to the procedure describedin Example I. The coating solutions were applied to the coils accordingto the procedure described in Example II. The coated coils wereimplanted into the vitreous chamber of rabbit eyes as follows. Theconjunctiva was dissected and pulled away from the incision site, and anincision was made into the eyes utilizing a needle stick through thesclera. A self-starting coil that included a sharp tip was utilized toinsert the coil into the vitreous chamber of the eye. The coils wereinserted until the cap of the coils abutted the outer surface of theeye, and the conjunctiva the was pulled over the cap at the conclusionof the insertion procedure.

Five of the Dose B and four of the Dose A coils were implanted for 29days. One of the Dose A coils was implanted for 11 days. Afterexplantation of the coils, the residual drug within the coated coils wasdetermined. The coatings were dissolved, and the drug and polymer wereseparated. The HPLC analysis consisted of a C18 column, a gradientelution using acetonitrile and deionized water and UV detection. Theresults from the solution containing the drug was compared to acalibration curve created from freshly prepared working standards. Theamount of drug released was calculated and plotted in FIG. 9.

TABLE V Coating Composition Applied to the Helical Coil. Weight of TA inCoil Dose Coating Parts by the Coated # Formulation Formulation weightComposition (μg) 1 A TA/pEVA/pBMA 50/10/40 950 2 A TA/pEVA/pBMA 50/10/40936 3 A TA/pEVA/pBMA 50/10/40 1012 4 A TA/pEVA/pBMA 50/10/40 911 5 ATA/pEVA/pBMA 50/10/40 932 6 B TA/pEVA/pBMA 50/27.5/22.5 981 7 BTA/pEVA/pBMA 50/27.5/22.5 974 8 B TA/pEVA/pBMA 50/27.5/22.5 957 9 BTA/pEVA/pBMA 50/27.5/22.5 975 10 B TA/pEVA/pBMA 50/27.5/22.5 965

Results indicated the amount of TA released within 11 and 29 days fromthe Dose A implanted coated coil was approximately 92 and 126 μg,respectively. The amount of TA released within 29 days from the Dose Bimplanted coil was approximately 275 μg. The amount of TA released fromthe “fast release” formulation, Dose B, was approximately 2.2 times theamount of TA released from the “slow release” formulation, Dose A.

The implanted materials appeared to be well tolerated by ocular tissuethroughout the 29-day follow-up period. No anterior or vitreous chamberinflammation was observed at either the 1-week or 4-week post-operativeexamination. Similarly, there was no elevation of intraocular pressureor conjunctival thinning associated with the implant.

Following explantation, the Dose A and Dose B coils were observed by 40×magnification light microscopy. No damage (scratches, delamination, orcracks) to the coatings was detected.

Other embodiments of this invention will be apparent to those skilled inthe art upon consideration of this specification or from practice of theinvention disclosed herein. Various omissions, modifications, andchanges to the principles and embodiments described herein may be madeby one skilled in the art without departing from the true scope andspirit of the invention which is indicated by the following claims. Allpatents, patent documents, and publications cited herein are herebyincorporated by reference as if individually incorporated.

1. An ocular controlled release bioactive agent delivery devicecomprising: a. a coil-shaped body member formed of a material that has across-section of 1 mm or less and does not include a lumen, the bodymember having a direction of extension, a longitudinal axis along thedirection of extension, and a proximal end and a distal end, wherein atleast a portion of the body member deviates from the direction ofextension; b. a polymeric coated composition in contact with at least aportion of the body member, the polymeric coated composition comprisinga first polymer, a second polymer, and a bioactive agent, wherein thefirst polymer comprises polyalkyl(meth)acrylate, and wherein the secondpolymer comprises poly(ethylene-co-vinyl acetate); and c. a cappositioned at the proximal end of the body member, wherein the bodymember has a length from its proximal end to its distal end of 1 cm orless, and the cap has a thickness that is 10% or less of the length ofthe body member, and wherein the bioactive agent is present in an amountin the range of 1 μg to 10 mg of bioactive agent per cm² of the coatedsurface of the device.
 2. The device according to claim 1 wherein thepolymeric coated composition is in contact with a portion of the bodymember that does not include the distal end.
 3. The device according toclaim 1 wherein the polymeric coated composition has a thickness, andwherein the thickness decreases towards the distal end of the bodymember.
 4. The device according to claim 1 wherein the body member isspiral.
 5. The device according to claim 1 wherein the body memberincludes surface configurations.
 6. The device according to claim 1wherein the cap has a thickness of 0.5 mm or less.
 7. The deviceaccording to claim 1 wherein the first polymer comprisespolyalkyl(meth)acrylate selected from the group consisting ofpolyalkyl(meth)acrylates having alkyl chain lengths in the range of 2 to8 carbons.
 8. The device according to claim 7 wherein the first polymercomprises poly(n-butyl)methacrylate.
 9. The device according to claim 1wherein the poly(ethylene-co-vinyl acetate) has a vinyl acetateconcentration in the range of 10% to 90% by weight.
 10. The deviceaccording to claim 1 further comprising a surface pretreatment.
 11. Thedevice according to claim 10 wherein the surface pretreatment is acompound selected from the group consisting of silane, polyurethane,parylene, or a combination thereof.
 12. The device according to claim 1wherein the polymeric coated composition is formulated to releasebioactive agent in a therapeutically effective amount for a period of 6months or more when the device is implanted in a patient's eye.
 13. Thedevice according to claim 1 wherein the distal end of the body member isspaced from the longitudinal axis.
 14. An ocular controlled releasebioactive agent delivery device comprising: a. a coil-shaped body memberformed of a material that has a cross-section of 1 mm or less, the bodymember having a direction of extension, a longitudinal axis along thedirection of extension, and a proximal end and a distal end, wherein atleast a portion of the body member deviates from the direction ofextension; b. a polymeric coated composition in contact with an externalsurface of the body member, the polymeric coated composition comprisinga first polymer, a second polymer, and a bioactive agent, wherein thefirst polymer comprises polyalkyl(meth)acrylate, and wherein the secondpolymer comprises poly(ethylene-co-vinyl acetate); and c. a cappositioned at the proximal end of the body member, wherein the bodymember has a length from its proximal end to its distal end of 1 cm orless, and the cap has a thickness that is 10% or less of the length ofthe body member, and wherein the bioactive agent is present in an amountin the range of 1 μg to 10 mg of bioactive agent per cm² of the coatedsurface of the device.
 15. The device according to claim 14 wherein theexternal surface of the body member in contact with the polymeric coatedcomposition does not include the distal end of the body member.
 16. Thedevice according to claim 14 wherein the polymeric coated compositionhas a thickness, and wherein the thickness decreases towards the distalend of the body member.
 17. The device according to claim 14 wherein thebody member is spiral.
 18. The device according to claim 14 wherein thebody member includes surface configurations.
 19. The device according toclaim 14 wherein at least a portion of the body member includes a lumenconfigured to serve as a delivery mechanism for delivery of a bioactiveagent to an implantation site upon implantation of the device in apatient's eye.
 20. The device according to claim 19 wherein the bodymember includes one or more apertures.
 21. The device according to claim19 wherein the bioactive agent to be delivered by the lumen is differentfrom the bioactive agent included in the coating composition.
 22. Thedevice according to claim 19 wherein the body member is formed of amaterial that is permeable or semi-permeable to the bioactive agent tobe delivered to a patient's eye from the lumen.
 23. The device accordingto claim 14 wherein the cap has a thickness of 0.5 mm or less.
 24. Thedevice according to claim 14 wherein the first polymer comprisespolyalkyl(meth)acrylate selected from the group consisting ofpolyalkyl(meth)acrylates having alkyl chain lengths in the range of 2 to8 carbons.
 25. The device according to claim 24 wherein the firstpolymer comprises poly(n-butyl)methacrylate.
 26. The device according toclaim 14 wherein the poly(ethylene-co-vinyl acetate) has a vinyl acetateconcentration in the range of 10% to 90% by weight.
 27. The deviceaccording to claim 14 further comprising a surface pretreatment.
 28. Thedevice according to claim 27 wherein the surface pretreatment is acompound selected from the group consisting of silane, polyurethane,parylene, or a combination thereof.
 29. The device according to claim 14wherein the polymeric coated composition is formulated to releasebioactive agent in a therapeutically effective amount for a period of 6months or more when the device is implanted in a patient's eye.
 30. Thedevice according to claim 14 wherein the distal end of the body memberis spaced from the longitudinal axis.
 31. An ocular controlled releasebioactive agent delivery device comprising: a. a coil-shaped body memberformed of a material having a cross-section of 1 mm or less, the bodymember having a direction of extension, a longitudinal axis along thedirection of extension, and a proximal end and a distal end, wherein atleast a portion of the body member deviates from the direction ofextension; b. a polymeric coated composition in contact with the bodymember, the polymeric coated composition comprising: (i) a first polymerselected from polyalkyl(meth)acrylate, (ii) a second polymer comprisingpoly(ethylene-co-vinyl acetate), and (iii) a bioactive agent selectedfrom triamcinolone acetonide, 13-cis retinoic acid, 5-fluorouridine, andcombinations thereof; and c. a cap positioned at the proximal end of thebody member, wherein the body member has a length from its proximal endto its distal end of 1 cm or less, and the cap has a thickness that is10% or less of the length of the body member, wherein the polymericcoated composition is formulated to release bioactive agent in atherapeutically effective amount for a period of 6 months or more whenthe device is implanted in a patient's eye, and wherein the bioactiveagent is present in an amount in the range of 1 μg to 10 mg of bioactiveagent per cm² of the coated surface of the device.
 32. The deviceaccording to claim 31 wherein the polymeric coated composition is incontact with a portion of the body member that does not include thedistal end.
 33. The device according to claim 31 wherein the polymericcoated composition has a thickness, and wherein the thickness decreasestowards the distal end of the body member.
 34. The device according toclaim 31 wherein the body member is spiral.
 35. The device according toclaim 31 wherein the body member includes surface configurations. 36.The device according to claim 31 wherein at least a portion of the bodymember includes a lumen configured to serve as a delivery mechanism fordelivery of a bioactive agent to an implantation site upon implantationof the device in a patient's eye.
 37. The device according to claim 36wherein the body member includes one or more apertures.
 38. The deviceaccording to claim 36 wherein the bioactive agent to be delivered by thelumen is different from the bioactive agent included in the coatingcomposition.
 39. The device according to claim 36 wherein the bodymember is formed of a material that is permeable or semi-permeable tothe bioactive agent to be delivered to a patient's eye from the lumen.40. The device according to claim 31 wherein the cap has a thickness of0.5 mm or less.
 41. The device according to claim 31 wherein the firstpolymer comprises polyalkyl(meth)acrylate selected from the groupconsisting of polyalkyl(meth)acrylates having alkyl chain lengths in therange of 2 to 8 carbons.
 42. The device according to claim 41 whereinthe first polymer comprises poly(n-butyl)methacrylate.
 43. The deviceaccording to claim 31 wherein the poly(ethylene-co-vinyl acetate) has avinyl acetate concentration in the range of 10% to 90% by weight. 44.The device according to claim 31 wherein the distal end of the bodymember is spaced from the longitudinal axis.
 45. The device according toclaim 31 further comprising a surface pretreatment.
 46. The deviceaccording to claim 45 wherein the surface pretreatment is a compoundselected from the group consisting of silane, polyurethane, parylene, ora combination thereof.
 47. An ocular controlled release bioactive agentdelivery device comprising: a. a coil-shaped body member formed of amaterial having a cross-section of 1 mm or less, the body member havinga direction of extension, a longitudinal axis along the direction ofextension, and a proximal end and a distal end, wherein at least aportion of the body member deviates from the direction of extension; b.a polymeric coated composition in contact with the body member, thepolymeric coated composition comprising a first polymer, a secondpolymer, and a bioactive agent; and c. a cap positioned at the proximalend of the body member, wherein the body member has a length from itsproximal end to its distal end of 1 cm or less, and the cap has athickness that is 10% or less of the length of the body member, whereinthe first polymer comprises polyalkyl(meth)acrylate, wherein the secondpolymer comprises poly(ethylene-co-vinyl acetate), wherein the bioactiveagent is present in an amount in the range of 1 μg to 10 mg of bioactiveagent per cm² of the coated surface of the device, and wherein thepolymeric coated composition is formulated to release bioactive agent ina therapeutically effective amount for a period of 6 months or more whenthe device is implanted in a patient's eye.
 48. The device according toclaim 47 wherein the polymeric coated composition is in contact with aportion of the body member that does not include the distal end.
 49. Thedevice according to claim 47 wherein the polymeric coated compositionhas a thickness, and wherein the thickness decreases towards the distalend of the body member.
 50. The device according to claim 47 wherein thebody member is spiral.
 51. The device according to claim 47 wherein thebody member includes surface configurations.
 52. The device according toclaim 47 wherein at least a portion of the body member includes a lumenconfigured to serve as a delivery mechanism for delivery of a bioactiveagent to an implantation site upon implantation of the device in apatient's eye.
 53. The device according to claim 47 wherein the bodymember includes one or more apertures.
 54. The device according to claim52 wherein the bioactive agent to be delivered by the lumen is differentfrom the bioactive agent included in the coating composition.
 55. Thedevice according to claim 47 wherein the body member is formed of amaterial that is permeable or semi-permeable to the bioactive agent tobe delivered to a patient's eye from the lumen.
 56. The device accordingto claim 47 wherein the cap has a thickness of 0.5 mm or less.
 57. Thedevice according to claim 47 wherein the first polymer comprisespolyalkyl(meth)acrylate selected from the group consisting ofpolyalkyl(meth)acrylates having alkyl chain lengths in the range of 2 to8 carbons.
 58. The device according to claim 57 wherein the firstpolymer comprises poly(n-butyl)methacrylate.
 59. The device according toclaim 47 wherein the poly(ethylene-co-vinyl acetate) has a vinyl acetateconcentration in the range of 10% to 90% by weight.
 60. The deviceaccording to claim 47 further comprising a surface pretreatment.
 61. Thedevice according to claim 60 wherein the surface pretreatment isselected from the group consisting of silane, polyurethane, parylene, orcombinations of any one or more of these.
 62. The device according toclaim 47 wherein the distal end of the body member is spaced from thelongitudinal axis.
 63. An ocular controlled release bioactive agentdelivery device comprising: a. a coil-shaped body member formed of amaterial having a cross-section of 1 mm or less, the body member havinga direction of extension, a longitudinal axis along the direction ofextension, and a proximal end and a distal end, wherein at least aportion of the body member deviates from the direction of extension; b.a polymeric coated composition in contact with the body member, thepolymeric coated composition comprising a first polymer, a secondpolymer, and triamcinolone acetonide; and c. a cap positioned at theproximal end of the body member, wherein the body member has a lengthfrom its proximal end to its distal end of 1 cm or less, and the cap hasa thickness that is 10% or less of the length of the body member,wherein the first polymer comprises polyalkyl(meth)acrylate, wherein thesecond polymer comprises poly(ethylene-co-vinyl acetate), wherein thepolymeric coated composition is formulated to release a therapeuticallyeffective amount of the triamcinolone acetonide when the device isimplanted in a patient's eye for a period of 6 months or more, andwherein the bioactive agent is present in an amount in the range of 1 μgto 10 mg of bioactive agent per cm² of the coated surface of the device.64. The device according to claim 63 wherein the polymeric coatedcomposition is in contact with a portion of the body member that doesnot include the distal end.
 65. The device according to claim 63 whereinthe polymeric coated composition has a thickness, and wherein thethickness decreases towards the distal end of the body member.
 66. Thedevice according to claim 63 wherein the body member is spiral.
 67. Thedevice according to claim 63 wherein the body member includes surfaceconfigurations.
 68. The device according to claim 63 wherein at least aportion of the body member includes a lumen configured to serve as adelivery mechanism for delivery of a bioactive agent to an implantationsite upon implantation of the device in a patient's eye.
 69. The deviceaccording to claim 68 wherein the body member includes one or moreapertures.
 70. The device according to claim 68 wherein the bioactiveagent to be delivered by the lumen is different from the bioactive agentincluded in the coating composition.
 71. The device according to claim68 wherein the body member is formed of a material that is permeable orsemi-permeable to the bioactive agent to be delivered to a patient's eyefrom the lumen.
 72. The device according to claim 63 wherein the cap hasa thickness of 0.5 mm or less.
 73. The device according to claim 63wherein the first polymer comprises polyalkyl(meth)acrylate selectedfrom the group consisting of polyalkyl(meth)acrylates having alkyl chainlengths in the range of 2 to 8 carbons.
 74. The device according toclaim 73 wherein the first polymer comprises poly(n-butyl)methacrylate.75. The device according to claim 63 wherein the poly(ethylene-co-vinylacetate) has a vinyl acetate concentration in the range of 10% to 90% byweight.
 76. The device according to claim 63 further comprising asurface pretreatment.
 77. The device according to claim 76 wherein thesurface pretreatment is a compound selected from the group consisting ofsilane, polyurethane, parylene, or a combination thereof.
 78. The deviceaccording to claim 63 wherein the distal end of the body member isspaced from the longitudinal axis.
 79. The device according to claim 63wherein the polymeric coated composition is formulated to release thetriamcinolone acetonide at an average release rate in the range of 0.5μg/day to 2 μg per day.
 80. The device according to claim 63 wherein thepolymeric coated composition is formulated to release the triamcinoloneacetonide at an average release rate in the range of 0.5 μg/day to 4.2μg/day in vitro.
 81. The device according to claim 63 wherein thepolymeric coated composition is formulated to release triamcinoloneacetonide in an amount in the range of 12.4% to 28.7% of totaltriamcinolone acetonide present in the composition, within 29 days afterimplantation in the patient's eye.
 82. The device according to claim 1wherein the bioactive agent is present within the polymeric coatedcomposition in an amount in the range of 100 μg to 1500 μg.
 83. Thedevice according to claim 14 wherein the bioactive agent is presentwithin the polymeric coated composition in an amount in the range of 100μg to 1500 μg.
 84. The device according to claim 31 wherein thebioactive agent is present within the polymeric coated composition in anamount in the range of 100 μg to 1500 μg.
 85. The device according toclaim 47 wherein the bioactive agent is present within the polymericcoated composition in an amount in the range of 100 μg to 1500 μg. 86.The device according to claim 63 wherein the triamcinolone acetonide ispresent within the polymeric coated composition in an amount in therange of 100 μg to 1500 μg.